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  • 1.
    Achour, Cyrinne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Bhattarai, Devi Prasad
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Esteva-Socias, Margalida
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Rodriguez-Barrueco, Ruth
    Malla, Sandhya
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Seier, Kerstin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Marchand, Virginie
    Motorine, Yuri
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marzese, Diego Matias
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Roman, Angel-Carlos
    Pich, Andreas
    Aguilo, Francesca
    Reshaping the role of METTL3 in breast tumorigenesisManuscript (preprint) (Other academic)
  • 2.
    Alhouayek, Mireille
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Sorti, René
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Role of pannexin-1 in the cellular uptake, release and hydrolysis of anandamide by T84 colon cancer cells2019In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 7622Article in journal (Refereed)
    Abstract [en]

    The large pore ion channel pannexin-1 (Panx1) has been reported to play a role in the cellular uptake and release of anandamide (AEA) in the hippocampus. It is not known whether this is a general mechanism or limited to the hippocampus. We have investigated this pharmacologically using T84 colon cancer cells. The cells expressed Panx1 at the mRNA level, and released ATP in a manner that could be reduced by treatment with the Panx1 inhibitors carbenoxolone and mefloquine and the Panxl substrate SR101. However, no significant effects of these compounds upon the uptake or hydrolysis of exogenously applied AEA was seen. Uptake by T84 cells of the other main endocannabinoid 2-arachidonoylglycerol and the AEA homologue palmitoylethanolamide was similarly not affected by carbenoxolone or mefloquine. Total release of tritium from [H-3]AEA-prelabelled T84 cells over 10 min was increased, rather than inhibited by carbenoxolone and mefloquine. Finally, AEA uptake by PC3 prostate cancer and SH-SY5Y neuroblastoma cells, which express functional Panx1 channels, was not inhibited by carbenoxolone. Thus, in contrast to the hippocampus, Panx1 does not appear to play a role in AEA uptake and release from the cells studied under the conditions used.

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  • 3.
    Andreae, Laura C.
    et al.
    MRC Centre for Developmental Neurobiology, King's College London, New Hunt's House, Guy's Campus, London, UK.
    Lumsden, Andrew
    MRC Centre for Developmental Neurobiology, King's College London, New Hunt's House, Guy's Campus, London, UK.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Chick Lrrn2, a novel downstream effector of Hoxb1 and Shh, functions in the selective targeting of rhombomere 4 motor neurons2009In: Neural development, ISSN 1749-8104, Vol. 4, p. 27-Article in journal (Refereed)
    Abstract [en]

    Background; Capricious is a Drosophila adhesion molecule that regulates specific targeting of a subset of motor neurons to their muscle target. We set out to identify whether one of its vertebrate homologues, Lrrn2, might play an analogous role in the chick.

    Results; We have shown that Lrrn2 is expressed from early development in the prospective rhombomere 4 (r4) of the chick hindbrain. Subsequently, its expression in the hindbrain becomes restricted to a specific group of motor neurons, the branchiomotor neurons of r4, and their pre-muscle target, the second branchial arch (BA2), along with other sites outside the hindbrain. Misexpression of the signalling molecule Sonic hedgehog (Shh) via in ovo electroporation results in upregulation of Lrrn2 exclusively in r4, while the combined expression of Hoxb1 and Shh is sufficient to induce ectopic Lrrn2 in r1/2. Misexpression of Lrrn2 in r2/3 results in axonal rerouting from the r2 exit point to the r4 exit point and BA2, suggesting a direct role in motor axon guidance.

    Conclusion; Lrrn2 acts downstream of Hoxb1 and plays a role in the selective targeting of r4 motor neurons to BA2.

  • 4. Andreae, Laura C
    et al.
    Peukert, Daniela
    Lumsden, Andrew
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Analysis of Lrrn1 expression and its relationship to neuromeric boundaries during chick neural development2007In: Neural Development, ISSN 1749-8104, Vol. 2, no 22, p. 1-16Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Drosophila leucine-rich repeat proteins Tartan (TRN) and Capricious (CAPS) mediate cell affinity differences during compartition of the wing imaginal disc. This study aims to identify and characterize the expression of a chick orthologue of TRN/CAPS and examine its potential function in relation to compartment boundaries in the vertebrate central nervous system.

    RESULTS: We identified a complementary DNA clone encoding Leucine-rich repeat neuronal 1 (Lrrn1), a single-pass transmembrane protein with 12 extracellular leucine-rich repeats most closely related to TRN/CAPS. Lrrn1 is dynamically expressed during chick development, being initially localized to the neural plate and tube, where it is restricted to the ventricular layer. It becomes downregulated in boundaries following their formation. In the mid-diencephalon, Lrrn1 expression prefigures the position of the anterior boundary of the zona limitans intrathalamica (ZLI). It becomes progressively downregulated from the presumptive ZLI just before the onset of expression of the signalling molecule Sonic hedgehog (Shh) within the ZLI. In the hindbrain, downregulation at rhombomere boundaries correlates with the emergence of specialized boundary cell populations, in which it is subsequently reactivated. Immunocolocalization studies confirm that Lrrn1 protein is endocytosed from the plasma membrane and is a component of the endosomal system, being concentrated within the early endosomal compartment.

    CONCLUSION: Chick Lrrn1 is expressed in ventricular layer neuroepithelial cells and is downregulated at boundary regions, where neurogenesis is known to be delayed, or inhibited. The timing of Lrrn1 downregulation correlates closely with the activation of signaling molecule expression at these boundaries. This expression is consistent with the emergence of secondary organizer properties at boundaries and its endosomal localisation suggests that Lrrn1 may regulate the subcellular localisation of specific components of signalling or cell-cell recognition pathways in neuroepithelial cells.

  • 5. Aparicio, S
    et al.
    Morrison, A
    Gould, A
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Chaudhuri, C
    Rigby, P
    Krumlauf, R
    Brenner, S
    Detecting conserved regulatory elements with the model genome of the Japanese puffer fish, Fugu rubripes.1995In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 92, no 5, p. 1684-1688Article in journal (Refereed)
    Abstract [en]

    Comparative vertebrate genome sequencing offers a powerful method for detecting conserved regulatory sequences. We propose that the compact genome of the teleost Fugu rubripes is well suited for this purpose. The evolutionary distance of teleosts from other vertebrates offers the maximum stringency for such evolutionary comparisons. To illustrate the comparative genome approach for F. rubripes, we use sequence comparisons between mouse and Fugu Hoxb-4 noncoding regions to identify conserved sequence blocks. We have used two approaches to test the function of these conserved blocks. In the first, homologous sequences were deleted from a mouse enhancer, resulting in a tissue-specific loss of activity when assayed in transgenic mice. In the second approach, Fugu DNA sequences showing homology to mouse sequences were tested for enhancer activity in transgenic mice. This strategy identified a neural element that mediates a subset of Hoxb-4 expression that is conserved between mammals and teleosts. The comparison of noncoding vertebrate sequences with those of Fugu, coupled to a transgenic bioassay, represents a general approach suitable for many genome projects.

  • 6.
    Bergman, J.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuolikainen, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Cytokine levels in interstitial brain fluid in progressive multiple sclerosis measured via intracerebral microdialysis2016In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, p. 511-511Article in journal (Refereed)
  • 7.
    Bergman, Joakim
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Burman, Joachim
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterberg, Henrik
    Jiltsova, Elena
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Intrathecal treatment trial of rituximab in progressive MS: An open-label phase 1b study2018In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 91, no 20, p. E1893-E1901Article in journal (Refereed)
    Abstract [en]

    Objectives To perform a phase 1b assessment of the safety and feasibility of intrathecally delivered rituximab as a treatment for progressive multiple sclerosis (PMS) and to evaluate the effect of treatment on disability and CSF biomarkers during a1-year follow-up period. Methods Three doses of rituximab (25 mg with a 1-week interval) were administered in 23 patients with PMS via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir. Follow-ups were performed at 1, 3, 6, 9, and 12 months. Results Mild to moderate vertigo and nausea were common but temporary adverse events associated with intrathecal rituximab infusion, which was otherwise well tolerated. The only severe adverse event was a case of low-virulent bacterial meningitis that was treated effectively. Of 7 clinical assessments, only 1 showed statistically significant improvement 1 year after treatment. No treatment effect was observed during the follow-up period among 6 CSF biomarkers. Conclusions Intrathecal administration of rituximab was well tolerated. However, it may involve a risk for injection-related infections. The lack of a control group precludes conclusions being drawn regarding treatment efficacy. ClinicalTrials.gov identifier NCT01719159. Classification of evidence This study provides Class IV evidence that intrathecal rituximab treatment is well tolerated and feasible in PMS but involves a risk of severe infections.

  • 8.
    Bergman, Joakim
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterberg, Henrik
    Blennow, Kaj
    Norgren, Niklas
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Anders
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Danderyd Hospital AB, Stockholm, Sweden..
    Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS2016In: Neurology: Neuroimmunology & Neuroinflammation, E-ISSN 2332-7812, Vol. 3, no 5, article id e271Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: In an ongoing, open-label, phase 1b study on the intrathecal administration of rituximab for progressive multiple sclerosis, an intraventricular catheter was inserted for drug delivery. The objective of this study was to characterize the limited white matter axonal injury evoked by catheter insertion by analyzing a panel of markers for tissue damage in CSF and serum.

    METHODS: Lumbar CSF and serum were collected before catheter insertion and at regular intervals during the follow-up period of 1 year. Levels of neurofilament light polypeptide (NF-L), glial fibrillary acidic protein, microtubule-associated protein tau, and S100 calcium binding protein B were measured in the CSF, and NF-L was also quantified in serum at each time point.

    RESULTS: One month after neurosurgical trauma, there was a distinct peak in NF-L concentration in both CSF and serum. In contrast, the biomarkers S100 calcium binding protein B, glial fibrillary acidic protein, and microtubule-associated protein tau did not show any significant changes. NF-L levels in both CSF and serum peaked at 1 month post surgery, returning to baseline after 6 to 9 months. A strong correlation was observed between the concentrations of NF-L in CSF and serum.

    CONCLUSIONS: The NF-L level, in CSF and serum, appears to be both a sensitive and specific marker for white matter axonal injury. This makes NF-L a valuable tool with which to evaluate acute white matter axonal damage in a clinical setting. Serum analysis of NF-L may become a convenient way to follow white matter axonal damage longitudinally.

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  • 9. Brend, Tim
    et al.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Summerbell, Dennis
    Rigby, Peter W J
    Multiple levels of transcriptional and post-transcriptional regulation are required to define the domain of Hoxb4 expression2003In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 130, no 12, p. 2717-2728Article in journal (Refereed)
    Abstract [en]

    Hox genes are key determinants of anteroposterior patterning of animal embryos, and spatially restricted expression of these genes is crucial to this function. In this study, we demonstrate that expression of Hoxb4 in the paraxial mesoderm of the mouse embryo is transcriptionally regulated in several distinct phases, and that multiple regulatory elements interact to maintain the complete expression domain throughout embryonic development. An enhancer located within the intron of the gene (region C) is sufficient for appropriate temporal activation of expression and the establishment of the correct anterior boundary in the paraxial mesoderm (somite 6/7). However, the Hoxb4 promoter is required to maintain this expression beyond 8.5 dpc. In addition, sequences within the 3' untranslated region (region B) are necessary specifically to maintain expression in somite 7 from 9.0 dpc onwards. Neither the promoter nor region B can direct somitic expression independently, indicating that the interaction of regulatory elements is crucial for the maintenance of the paraxial mesoderm domain of Hoxb4 expression. We further report that the domain of Hoxb4 expression is restricted by regulating transcript stability in the paraxial mesoderm and by selective translation and/or degradation of protein in the neural tube. Moreover, the absence of Hoxb4 3'-untranslated sequences from transgene transcripts leads to inappropriate expression of some Hoxb4 transgenes in posterior somites, indicating that there are sequences within region B that are important for both transcriptional and post-transcriptional regulation.

  • 10. Broom, Emma R
    et al.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Butts, Thomas
    Campo-Paysaa, Florent
    Wingate, Richard J T
    The roof plate boundary is a bi-directional organiser of dorsal neural tube and choroid plexus development.2012In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, no 22, p. 4261-4270Article in journal (Refereed)
    Abstract [en]

    The roof plate is a signalling centre positioned at the dorsal midline of the central nervous system and generates dorsalising morphogenic signals along the length of the neuraxis. Within cranial ventricles, the roof plate gives rise to choroid plexus, which regulates the internal environment of the developing and adult brain and spinal cord via the secretion of cerebrospinal fluid. Using the fourth ventricle as our model, we show that the organiser properties of the roof plate are determined by its boundaries with the adjacent neuroepithelium. Through a combination of in ovo transplantation, co-culture and electroporation techniques in chick embryos between embryonic days 3 and 6, we demonstrate that organiser properties are maintained by interactions between the non-neural roof plate and the neural rhombic lip. At the molecular level, this interaction is mediated by Delta-Notch signalling and upregulation of the chick homologue of Hes1: chairy2. Gain- and loss-of-function approaches reveal that cdelta1 is both necessary and sufficient for organiser function. Our results also demonstrate that while chairy2 is specifically required for the maintenance of the organiser, its ectopic expression is not sufficient to recapitulate organiser properties. Expression of atonal1 in the rhombic lip adjacent at the roof plate boundary is acutely dependent on both boundary cell interactions and Delta-Notch signalling. Correspondingly, the roof plate boundary organiser also signals to the roof plate itself to specify the expression of early choroid plexus markers. Thus, the roof plate boundary organiser signals bi-directionally to acutely coordinate the development of adjacent neural and non-neural tissues.

  • 11. Coutinho, Ana P
    et al.
    Borday, Caroline
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jungbluth, Stefan
    Champagnat, Jean
    Lumsden, Andrew
    Fortin, Gilles
    Induction of a parafacial rhythm generator by rhombomere 3 in the chick embryo.2004In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 24, no 42, p. 9383-9390Article in journal (Refereed)
    Abstract [en]

    Observations of knock-out mice suggest that breathing at birth requires correct development of a specific hindbrain territory corresponding to rhombomeres (r) 3 and 4. Focusing on this territory, we examined the development of a neuronal rhythm generator in the chick embryo. We show that rhythmic activity in r4 is inducible after developmental stage 10 through interaction with r3. Although the nature of this interaction remains obscure, we find that the expression of Krox20, a segmentation gene responsible for specifying r3 and r5, is sufficient to endow other rhombomeres with the capacity to induce rhythmic activity in r4. Induction is robust, because it can be reproduced with r2 and r6 instead of r4 and with any hindbrain territory that normally expresses Krox20 (r3, r5) or can be forced to do so (r1, r4). Interestingly, the interaction between r4 and r3/r5 that results in rhythm production can only take place through the anterior border of r4, revealing a heretofore unsuspected polarity in individual rhombomeres. The r4 rhythm generator appears to be homologous to a murine respiratory parafacial neuronal system developing in r4 under the control of Krox20 and Hoxa1. These results identify a late role for Krox20 at the onset of neurogenesis.

  • 12. Cunningham, Thomas J.
    et al.
    Fisher, Elizabeth
    Fratta, Pietro
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    DNA Editing for Amyotrophic Lateral Sclerosis: Leading Off First Base2020In: The CRISPR Journal, ISSN 2573-1599, Vol. 3, no 2, p. 75-77Article in journal (Other academic)
    Abstract [en]

    Gene therapy in a mouse model for amyotrophic lateral sclerosis (ALS) illustrates the rapid deployment of base editing in therapeutic modeling of neurodegenerative disease.

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  • 13. Devoy, Anny
    et al.
    Price, Georgia
    De Giorgio, Francesca
    Bunton-Stasyshyn, Rosie
    Thompson, David
    Gasco, Samanta
    Allan, Alasdair
    Codner, Gemma F.
    Nair, Remya R.
    Tibbit, Charlotte
    McLeod, Ross
    Ali, Zeinab
    Noda, Judith
    Marrero-Gagliardi, Alessandro
    Brito-Armas, José M.
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Öztürk, Muhammet M.
    Simon, Michelle
    O'Neill, Edward
    Bryce-Smith, Sam
    Harrison, Jackie
    Atkins, Gemma
    Corrochano, Silvia
    Stewart, Michelle
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Teboul, Lydia
    Acevedo-Arozena, Abraham
    Fisher, Elizabeth M. C.
    Cunningham, Thomas J.
    Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models2021In: iScience, E-ISSN 2589-0042 , Vol. 24, no 12, article id 103463Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanized knockin mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43), and Fus, with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing. Extensive analysis shows that homozygous humanized animals only express human protein at endogenous levels. Characterization of humanized FUS animals showed that they are phenotypically normal throughout their lifespan. These humanized strains are vital for preclinical assessment of interventions and serve as templates for the addition of coding or non-coding human ALS/FTD mutations to dissect disease pathomechanisms, in a physiological context.

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  • 14.
    Falker-Gieske, Clemens
    et al.
    Department of Animal Sciences, Georg-August-University, Göttingen, Germany.
    Paul, Nora-Fabienne
    Department of Animal Sciences, Georg-August-University, Göttingen, Germany.
    Spourita, Maria
    Department of Animal Sciences, Georg-August-University, Göttingen, Germany.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gustmann, Karolin
    Department of Animal Sciences, Georg-August-University, Göttingen, Germany.
    Tetens, Jens
    Department of Animal Sciences, Georg-August-University, Göttingen, Germany; Center for Integrated Breeding Research, Georg-August-University, Göttingen, Germany.
    Resistance to chicken amyloid arthropathy is associated with a dysfunctional mutation in serum amyloid A2023In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 37, no 1, article id e22700Article in journal (Refereed)
    Abstract [en]

    Chicken amyloid arthropathy is a debilitating disease with a major impact on animal welfare. Since the disease is triggered by bacterial infection, preventative treatment also contributes to the widespread overuse of antibiotics. Bacterial infection initiates an acute phase response including increased serum amyloid A (SAA) production by the liver. SAA accumulates at sites of infection and in particular in large joints of affected birds. Interestingly, white egg-laying chickens (WL) are resistant to the disease whilst brown egg-laying chickens (BL) are most affected. Disease susceptibility has an immunological basis but the possible contribution of underlying genetic risk factors is not understood. Using a whole genome sequencing approach, we discovered a novel variant in the SAA gene in WL, which is predicted to result in an arginine to serine substitution at position 90 (SAA.R90S). Surprisingly, when overexpressed in chicken hepatocellular carcinoma cells, SAA.R90S was expressed at a higher rate and secreted to a greater degree than the wild-type SAA protein. Moreover, RNASeq analysis showed that the R90S mutant exerted a differential effect on the expression of core transcription factors linked to cell fate determination and cell differentiation. Comparative analysis of gene expression in murine CD4 T-cells stimulated with IL-6/SAA, suggests that SAA.R90S might block an induced cell fate change toward pro-inflammatory T helper 17 cells, which are required for immunological protection against pathogenic bacteria during an acute phase response. Our results provide first mechanistic insights into the genetic resistance of WL to amyloid arthropathy and could be applied to commercial layer breeding programs to improve animal welfare and reduce the negative effects of the overuse of antibiotics.

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  • 15.
    Forsgren, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lehmann, Manuela
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Weygandt Mathis, Mackenzie
    Keskin, Isil
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nijssen, Jik
    Lowry, Emily
    Garcia, Alejandro
    Sandoe, Jackson
    Hedlund, Eva
    Wichterle, Hynek
    Henderson, Christopher
    Eggan, Kevin
    Kiskinis, Evangelos
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Enhanced protein misfolding in patient-derived models of amyotrophic lateral sclerosisManuscript (preprint) (Other (popular science, discussion, etc.))
  • 16.
    Forsgren, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nordin, Frida
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Danielsson, Jens
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    A Novel mutation D96Mfs*8 in SOD1 identified in a Swedish ALS patient results in a truncated and heavily aggregation-prone proteinManuscript (preprint) (Other (popular science, discussion, etc.))
  • 17.
    Gilthorpe, Jonathan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Oozeer, Fazal
    Nash, Julia
    Calvo, Margarita
    Bennett, David Lh
    Lumsden, Andrew
    Pini, Adrian
    Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia.2013In: F1000Research, ISSN 2046-1402, Vol. 2, no 148Article in journal (Refereed)
    Abstract [en]

    In neurodegenerative conditions and following brain trauma it is not understood why neurons die while astrocytes and microglia survive and adopt pro-inflammatory phenotypes. We show here that the damaged adult brain releases diffusible factors that can kill cortical neurons and we have identified histone H1 as a major extracellular candidate that causes neurotoxicity and activation of the innate immune system. Extracellular core histones H2A, H2B H3 and H4 were not neurotoxic. Innate immunity in the central nervous system is mediated through microglial cells and we show here for the first time that histone H1 promotes their survival, up-regulates MHC class II antigen expression and is a powerful microglial chemoattractant. We propose that when the central nervous system is degenerating, histone H1 drives a positive feedback loop that drives further degeneration and activation of immune defences which can themselves be damaging. We suggest that histone H1 acts as an antimicrobial peptide and kills neurons through mitochondrial damage and apoptosis.

  • 18.
    Gilthorpe, Jonathan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Papantoniou, Elli-Kalliopi
    Chédotal, Alain
    Lumsden, Andrew
    Wingate, Richard J T
    The migration of cerebellar rhombic lip derivatives.2002In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 129, no 20, p. 4719-4728Article in journal (Refereed)
    Abstract [en]

    We have used cell labelling, co-culture and time-lapse confocal microscopy to investigate tangential neuronal migration from the rhombic lip. Cerebellar rhombic lip derivatives demonstrate a temporal organisation with respect to their morphology and response to migration cues. Early born cells, which migrate into ventral rhombomere 1, have a single long leading process that turns at the midline and becomes an axon. Later born granule cell precursors also migrate ventrally but halt at the lateral edge of the cerebellum, correlating with a loss of sensitivity to netrin 1 and expression of Robo2. The rhombic lip and ventral midline express Slit2 and both early and late migrants are repelled by sources of Slit2 in co-culture. These studies reveal an intimate relationship between birthdate, response to migration cues and neuronal fate in an identified population of migratory cells. The use of axons in navigating cell movement suggests that tangential migration is an elaboration of the normal process of axon extension.

  • 19.
    Gilthorpe, Jonathan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Rigby, P W
    Reporter genes for the study of transcriptional regulation in transgenic mouse embryos.1999In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 97, p. 159-182Article in journal (Refereed)
  • 20.
    Gilthorpe, Jonathan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vandromme, Marie
    Brend, Tim
    Gutman, Alejandro
    Summerbell, Dennis
    Totty, Nick
    Rigby, Peter W J
    Spatially specific expression of Hoxb4 is dependent on the ubiquitous transcription factor NFY.2002In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 129, no 16, p. 3887-99Article in journal (Refereed)
    Abstract [en]

    Understanding how boundaries and domains of Hox gene expression are determined is critical to elucidating the means by which the embryo is patterned along the anteroposterior axis. We have performed a detailed analysis of the mouse Hoxb4 intron enhancer to identify upstream transcriptional regulators. In the context of an heterologous promoter, this enhancer can establish the appropriate anterior boundary of mesodermal expression but is unable to maintain it, showing that a specific interaction with its own promoter is important for maintenance. Enhancer function depends on a motif that contains overlapping binding sites for the transcription factors NFY and YY1. Specific mutations that either abolish or reduce NFY binding show that it is crucial for enhancer activity. The NFY/YY1 motif is reiterated in the Hoxb4 promoter and is known to be required for its activity. As these two factors are able to mediate opposing transcriptional effects by reorganizing the local chromatin environment, the relative levels of NFY and YY1 binding could represent a mechanism for balancing activation and repression of Hoxb4 through the same site.

  • 21.
    Groza, Paula
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Kumari, Kanchan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Destefanis, Eliana
    Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Italy.
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Marchand, Virginie
    IMoPA (UMR7365), and INSERM, IBSLor (UMS2008/US40), Epitranscriptomics and RNA Sequencing Core Facility, University of Lorraine, France.
    Motorin, Yuri
    IMoPA (UMR7365), and INSERM, IBSLor (UMS2008/US40), Epitranscriptomics and RNA Sequencing Core Facility, University of Lorraine, France.
    Mateus, André
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Dassi, Erik
    Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Italy.
    Schott, Johanna
    Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, and Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3), Mannheim Cancer Center (MCC), Medical Faculty Mannheim, Heidelberg University, Germany.
    Tuorto, Francesca
    Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, and Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3), Mannheim Cancer Center (MCC), Medical Faculty Mannheim, Heidelberg University, Germany.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Fibrillarin regulates oncogenic protein pools and ribosome protein composition in triple-negative breast cancerManuscript (preprint) (Other academic)
  • 22.
    Gutman, Alejandro
    et al.
    Laboratory of Eukaryotic Molecular Genetics, MRC National Institute for Medical Research, London, England.
    Gilthorpe, Jonathan
    Laboratory of Eukaryotic Molecular Genetics, MRC National Institute for Medical Research, London, England.
    Rigby, PETER W. J.
    Laboratory of Eukaryotic Molecular Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, England.
    Multiple positive and negative regulatory elements in the promoter of the mouse homeobox gene Hoxb-4.1994In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 14, no 12, p. 8143-8154Article in journal (Refereed)
    Abstract [en]

    Mouse Hoxb-4 (Hox-2.6) is a homeobox gene that belongs to a family which also includes Hoxa-4, Hoxc-4, and Hoxd-4 and that is related to the Deformed gene in Drosophila melanogaster. We have determined the sequence of 1.2 kb of 5' flanking DNA of mouse Hoxb-4 and by nuclease S1 and primer extension experiments identified two transcription start sites, P1 and P2, 285 and 207 nucleotides upstream of the ATG initiator codon, respectively. We have shown that this region harbors two independent promoters which drive CAT expression in several different cell lines with various efficiencies, suggesting that they are subject to cell-type-specific regulation. Through detailed mutational analysis, we have identified several cis-regulatory elements, located upstream and downstream of the transcription start sites. They include two cell-type-specific negative regulatory elements, which are more active in F9 embryonal carcinoma cells than in neuroblastoma cells (regions a and d at -226 to -186 and +169 to +205, respectively). An additional negative regulatory element has been delimited (region b between +22 and +113). Positive regulation is achieved by binding of HoxTF, a previously unknown factor, to the sequence GCCATTGG (+148 to +155) that is essential for efficient Hoxb-4 expression. We have also defined the minimal promoter sequences and found that they include two 12-bp initiator elements centered around each transcription start site. The complex architecture of the Hoxb-4 promoter provides the framework for fine-tuned transcriptional regulation during embryonic development.

  • 23.
    Günther, René
    et al.
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Dresden, Germany.
    Pal, Arun
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Dresden High Magnetic Field Laboratory (HLD), Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Zimyanin, Vitaly L.
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Department of Molecular Physiology and Biological Physics, University of Virginia, VA, Charlottesville, United States.
    Liehr, Maria
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.
    von Neubeck, Cläre
    German Cancer Consortium(DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay—National Center for Radiation Research in Oncology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Clinic for Particle Therapy, West German Proton Therapy Centre Essen (WPE) gGmbH, University Medical Centre of Essen, Essen, Germany.
    Krause, Mechthild
    German Cancer Consortium(DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay—National Center for Radiation Research in Oncology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden—Rossendorf, Institute of Radiooncology—OncoRay, Dresden, Germany; Department of Radiotherapy and Radiation Oncology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.
    Parab, Mrudula G.
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.
    Petri, Susanne
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Kalmbach, Norman
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Sterneckert, Jared
    Center for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Wegner, Florian
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Hermann, Andreas
    Translational Neurodegeneration Section, Albrecht-Kossel, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany.
    Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 7, article id 1246Article in journal (Refereed)
    Abstract [en]

    Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated SOD1 mutations (D90Ahom, R115Ghet or A4Vhet) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90Ahom MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115Ghet and A4Vhet mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS.

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  • 24.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Elin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lange, Dale J.
    Synofzik, Matthis
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Low oxygen tension induces misfolding and aggregation of superoxide dismutase in ALS patient-derived motor neuronsManuscript (preprint) (Other academic)
  • 25.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Elin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lange, Dale J.
    Weber, Markus
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Synofzik, Matthis
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 2, article id e0150133Article in journal (Refereed)
    Abstract [en]

    Mutations in superoxide dismutase-1 (SOD1) are a common known cause of amyotrophic lateral sclerosis (ALS). The neurotoxicity of mutant SOD1s is most likely caused by misfolded molecular species, but disease pathogenesis is still not understood. Proposed mechanisms include impaired mitochondrial function, induction of endoplasmic reticulum stress, reduction in the activities of the proteasome and autophagy, and the formation of neurotoxic aggregates. Here we examined whether perturbations in these cellular pathways in turn influence levels of misfolded SOD1 species, potentially amplifying neurotoxicity. For the study we used fibroblasts, which express SOD1 at physiological levels under regulation of the native promoter. The cells were derived from ALS patients expressing 9 different SOD1 mutants of widely variable molecular characteristics, as well as from patients carrying the GGGGCC-repeat-expansion in C9orf72 and from non-disease controls. A specific ELISA was used to quantify soluble, misfolded SOD1, and aggregated SOD1 was analysed by western blotting. Misfolded SOD1 was detected in all lines. Levels were found to be much lower in non-disease control and the non-SOD1 C9orf72 ALS lines. This enabled us to validate patient fibroblasts for use in subsequent perturbation studies. Mitochondrial inhibition, endoplasmic reticulum stress or autophagy inhibition did not affect soluble misfolded SOD1 and in most cases, detergent-resistant SOD1 aggregates were not detected. However, proteasome inhibition led to uniformly large increases in misfolded SOD1 levels in all cell lines and an increase in SOD1 aggregation in some. Thus the ubiquitin-proteasome pathway is a principal determinant of misfolded SOD1 levels in cells derived both from patients and controls and a decline in activity with aging could be one of the factors behind the mid-to late-life onset of inherited ALS.

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  • 26.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsgren, Elin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lehmann, Manuela
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lange, Dale J.
    Synofzik, Matthis
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension2019In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 138, no 1, p. 85-101Article in journal (Refereed)
    Abstract [en]

    Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Mainly located to the reducing cytosol, mature SOD1 contains an oxidized disulfide bond that is important for its stability. Since O2 is required for formation of the bond, we reasoned that low O2 tension might be a risk factor for the pathological changes associated with ALS development. By combining biochemical approaches in an extensive range of genetically distinct patient-derived cell lines, we show that the disulfide bond is an Achilles heel of the SOD1 protein. Culture of patient-derived fibroblasts, astrocytes, and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under low oxygen tensions caused reductive bond cleavage and increases in disordered SOD1. The effects were greatest in cells derived from patients carrying ALS-linked mutations in SOD1. However, significant increases also occurred in wild-type SOD1 in cultures derived from non-disease controls, and patients carrying mutations in other common ALS-linked genes. Compared to fibroblasts, MNACs showed far greater increases in SOD1 disorder and even aggregation of mutant SOD1s, in line with the vulnerability of the motor system to SOD1-mediated neurotoxicity. Our results show for the first time that O2 tension is a principal determinant of SOD1 stability in human patient-derived cells. Furthermore, we provide a mechanism by which non-genetic risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could promote disease initiation and progression.

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  • 27. Khademi, Mohsen
    et al.
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Al Nimer, Faiez
    Harris, Robert
    Andersson, Magnus
    Brundin, Lou
    Piehl, Fredrik
    Olsson, Tomas
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Multivariate analysis of inflammatory and neuronal injury markers in cerebrospinal fluid of multiple sclerosis: higher levels are associated with younger age2012In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 253, no 1-2, p. 100-100Article in journal (Other academic)
  • 28. Khademi, Mohsen
    et al.
    Dring, Ann M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Al Nimer, Faiez
    Harris, Robert A.
    Andersson, Magnus
    Brundin, Lou
    Piehl, Fredrik
    Olsson, Tomas
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Intense Inflammation and Nerve Damage in Early Multiple Sclerosis Subsides at Older Age: A Reflection by Cerebrospinal Fluid Biomarkers2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 5, p. e63172-Article in journal (Refereed)
    Abstract [en]

    Inflammatory mediators have crucial roles in leukocyte recruitment and subsequent central nervous system (CNS) neuroinflammation. The extent of neuronal injury and axonal loss are associated with the degree of CNS inflammation and determine physical disability in multiple sclerosis (MS). The aim of this study was to explore possible associations between a panel of selected cerebrospinal fluid biomarkers and robust clinical and demographic parameters in a large cohort of patients with MS and controls (n = 1066) using data-driven multivariate analysis. Levels of matrix metalloproteinase 9 (MMP9), chemokine (C-X-C motif) ligand 13 (CXCL13), osteopontin (OPN) and neurofilament-light chain (NFL) were measured by ELISA in 548 subjects comprising different MS subtypes (relapsing-remitting, secondary progressive and primary progressive), clinically isolated syndrome and persons with other neurological diseases with or without signs of inflammation/infection. Principal component analyses and orthogonal partial least squares methods were used for unsupervised and supervised interrogation of the data. Models were validated using data from a further 518 subjects in which one or more of the four selected markers were measured. There was a significant association between increased patient age and lower levels of CXCL13, MMP9 and NFL. CXCL13 levels correlated well with MMP9 in the younger age groups, but less so in older patients, and after approximately 54 years of age the levels of CXCL13 and MMP9 were consistently low. CXCL13 and MMP9 levels also correlated well with both NFL and OPN in younger patients. We demonstrate a strong effect of age on both inflammatory and neurodegenerative biomarkers in a large cohort of MS patients. The findings support an early use of adequate immunomodulatory disease modifying drugs, especially in younger patients, and may provide a biological explanation for the relative inefficacy of such treatments in older patients at later disease stages.

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  • 29.
    Knyazeva, Anastasia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Corkery, Dale
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Shankar, Kasturika
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Herzog, Laura K.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Zhang, Xuepei
    Chemical Proteomics Core Facility, Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Chemical Proteomics Unit, SciLifeLab, Stockholm, Sweden; Chemical Proteomics, Swedish National Infrastructure for Biological Mass Spectrometry (BioMS), Stockholm, Sweden.
    Singh, Birendra
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Niggemeyer, Georg
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
    Grill, David
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gaetani, Massimiliano
    Chemical Proteomics Core Facility, Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Chemical Proteomics Unit, SciLifeLab, Stockholm, Sweden; Chemical Proteomics, Swedish National Infrastructure for Biological Mass Spectrometry (BioMS), Stockholm, Sweden.
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Waldmann, Herbert
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany; Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany.
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Chemogenetic inhibition of IST1-CHMP1B interaction impairs endosomal recycling and promotes unconventional LC3 lipidation at stalled endosomesManuscript (preprint) (Other academic)
  • 30.
    Knyazeva, Anastasia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Science for Life Laboratory, Umeå University, Umeå, Sweden.
    Li, Shuang
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Science for Life Laboratory, Umeå University, Umeå, Sweden.
    Corkery, Dale P.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Science for Life Laboratory, Umeå University, Umeå, Sweden.
    Shankar, Kasturika
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Herzog, Laura K.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Zhang, Xuepei
    Chemical Proteomics Core Facility, Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Chemical Proteomics Unit, Science for Life Laboratory, Stockholm, Sweden; Chemical Proteomics, Swedish National Infrastructure for Biological Mass Spectrometry, Stockholm, Sweden.
    Singh, Birendra
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Niggemeyer, Georg
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
    Grill, David
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gaetani, Massimiliano
    Chemical Proteomics Core Facility, Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Chemical Proteomics Unit, Science for Life Laboratory, Stockholm, Sweden; Chemical Proteomics, Swedish National Infrastructure for Biological Mass Spectrometry, Stockholm, Sweden.
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Waldmann, Herbert
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany; Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany.
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Science for Life Laboratory, Umeå University, Umeå, Sweden.
    A chemical inhibitor of IST1-CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation2024In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 121, no 17, article id e2317680121Article in journal (Refereed)
    Abstract [en]

    The endosomal sorting complex required for transport (ESCRT) machinery constitutes multisubunit protein complexes that play an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, including cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair, and autophagy. Given the versatile functionality of ESCRTs, and the intricate organizational structure of the ESCRT machinery, the targeted modulation of distinct ESCRT complexes is considerably challenging. This study presents a pseudonatural product targeting IST1-CHMP1B within the ESCRT-III complexes. The compound specifically disrupts the interaction between IST1 and CHMP1B, thereby inhibiting the formation of IST1-CHMP1B copolymers essential for normal-topology membrane scission events. While the compound has no impact on cytokinesis, MVB sorting, or biogenesis of extracellular vesicles, it rapidly inhibits transferrin receptor recycling in cells, resulting in the accumulation of transferrin in stalled sorting endosomes. Stalled endosomes become decorated by lipidated LC3, suggesting a link between noncanonical LC3 lipidation and inhibition of the IST1-CHMP1B complex.

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  • 31.
    Lehmann, Manuela
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Marklund, Matthew
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bolender, Anna-Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Bidhendi, Elaheh E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice2020In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 8, no 1, article id 161Article in journal (Refereed)
    Abstract [en]

    Increasing evidence suggests that propagation of the motor neuron disease amyotrophic lateral sclerosis (ALS) involves the pathogenic aggregation of disease-associated proteins that spread in a prion-like manner. We have identified two aggregate strains of human superoxide dismutase 1 (hSOD1) that arise in the CNS of transgenic mouse models of SOD1-mediated ALS. Both strains transmit template-directed aggregation and premature fatal paralysis when inoculated into the spinal cord of adult hSOD1 transgenic mice. This spread of pathogenic aggregation could be a potential target for immunotherapeutic intervention. Here we generated mouse monoclonal antibodies (mAbs) directed to exposed epitopes in hSOD1 aggregate strains and identified an aggregate selective mAb that targets the aa 143–153 C-terminal extremity of hSOD1 (αSOD1143–153). Both pre-incubation of seeds with αSOD1143–153 prior to inoculation, and weekly intraperitoneal (i.p.) administration attenuated transmission of pathogenic aggregation and prolonged the survival of seed-inoculated hSOD1G85R Tg mice. In contrast, administration of a mAb targeting aa 65–72 (αSOD165–72), which exhibits high affinity towards monomeric disordered hSOD1, had an adverse effect and aggravated seed induced premature ALS-like disease. Although the mAbs reached similar concentrations in CSF, only αSOD1143–153 was found in association with aggregated hSOD1 in spinal cord homogenates. Our results suggest that an aggregate-selective immunotherapeutic approach may suppress seeded transmission of pathogenic aggregation in ALS. However, long-term administration of αSOD1143–153 was unable to prolong the lifespan of non-inoculated hSOD1G85R Tg mice. Thus, spontaneously initiated hSOD1 aggregation in spinal motor neurons may be poorly accessible to therapeutic antibodies.

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  • 32.
    Leppert, Axel
    et al.
    Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Solna, Sweden.
    Chen, Gefei
    Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
    Lianoudaki, Danai
    Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Solna, Sweden.
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Zhong, Xueying
    Division of Structural Biotechnology, Department of Biomedical Engineering and Health Systems, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), KTH Royal Institute of Technology, Huddinge, Sweden.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Landreh, Michael
    Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Solna, Sweden.
    Johansson, Jan
    Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
    ATP-independent molecular chaperone activity generated under reducing conditions2022In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 31, no 8, article id e4378Article in journal (Refereed)
    Abstract [en]

    Molecular chaperones are essential to maintain proteostasis. While the functions of intracellular molecular chaperones that oversee protein synthesis, folding and aggregation, are established, those specialized to work in the extracellular environment are less understood. Extracellular proteins reside in a considerably more oxidizing milieu than cytoplasmic proteins and are stabilized by abundant disulfide bonds. Hence, extracellular proteins are potentially destabilized and sensitive to aggregation under reducing conditions. We combine biochemical and mass spectrometry experiments and elucidate that the molecular chaperone functions of the extracellular protein domain Bri2 BRICHOS only appear under reducing conditions, through the assembly of monomers into large polydisperse oligomers by an intra- to intermolecular disulfide bond relay mechanism. Chaperone-active assemblies of the Bri2 BRICHOS domain are efficiently generated by physiological thiol-containing compounds and proteins, and appear in parallel with reduction-induced aggregation of extracellular proteins. Our results give insights into how potent chaperone activity can be generated from inactive precursors under conditions that are destabilizing to most extracellular proteins and thereby support protein stability/folding in the extracellular space.

    Significance: Chaperones are essential to cells as they counteract toxic consequences of protein misfolding particularly under stress conditions. Our work describes a novel activation mechanism of an extracellular molecular chaperone domain, called Bri2 BRICHOS. This mechanism is based on reducing conditions that initiate small subunits to assemble into large oligomers via a disulfide relay mechanism. Activated Bri2 BRICHOS inhibits reduction-induced aggregation of extracellular proteins and could be a means to boost proteostasis in the extracellular environment upon reductive stress.

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  • 33.
    Lindqvist, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Kurhade, Chaitanya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cell-type- and region-specific restriction of neurotropic flavivirus infection by viperin2018In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 80Article in journal (Refereed)
    Abstract [en]

    Background: Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against flavivirus infection. IFNs elicit the concerted action of numerous interferon-stimulated genes (ISGs) to restrict both virus infection and replication. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple flaviviruses in vitro. Its activity in vivo restricts neurotropic infections to specific regions of the central nervous system (CNS). However, the cell types in which viperin activity is required are unknown. Here we have examined both the regional and cell-type specificity of viperin in the defense against infection by several model neurotropic flaviviruses.

    Methods: Viral burden and IFN induction were analyzed in vivo in wild-type and viperin(-/-) mice infected with Langat virus (LGTV). The effects of IFN pretreatment were tested in vitro in primary neural cultures from different brain regions in response to infection with tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Zika virus (ZIKV).

    Results: Viperin activity restricted nonlethal LGTV infection in the spleen and the olfactory bulb following infection via a peripheral route. Viperin activity was also necessary to restrict LGTV replication in the olfactory bulb and the cerebrum following CNS infection, but not in the cerebellum. In vitro, viperin could restrict TBEV replication in primary cortical neurons, but not in the cerebellar granule cell neurons. Interferon-induced viperin was also very important in primary cortical neurons to control TBEV, WNV, and ZIKV.

    Conclusions: Our findings show that viperin restricts replication of neurotropic flaviviruses in the CNS in a region- and cell-type-specific manner. The most important sites of activity are the olfactory bulb and cerebrum. Activity within the cerebrum is required in the cortical neurons in order to restrict spread. This study exemplifies cell type and regional diversity of the IFN response within the CNS and shows the importance of a potent broad-spectrum antiviral ISG.

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  • 34.
    Lindqvist, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kurhade, Chaitanya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Viperin restrict neurotropic flavivirus infection in cell type and region-specific mannerManuscript (preprint) (Other academic)
  • 35.
    Lindqvist, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Mundt, Filip
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Woelfel, Silke
    Gekara, Nelson O.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kroeger, Andrea
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects2016In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 13, article id 277Article in journal (Refereed)
    Abstract [en]

    Background: Neurotropic flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne flavivirus infection. However, the cells responsible for mounting this protective response are not defined. Methods: Primary astrocytes were isolated from wild-type (WT) and interferon alpha receptor knock out (IFNAR(-/-)) mice and infected with neurotropic flaviviruses. Viral replication and spread, IFN induction and response, and cellular viability were analyzed. Transcriptional levels in primary astrocytes treated with interferon or supernatant from virus-infected cells were analyzed by RNA sequencing and evaluated by different bioinformatics tools. Results: Here, we show that astrocytes control viral replication of different TBEV strains, JEV, WNV, and ZIKV. In contrast to fibroblast, astrocytes mount a rapid interferon response and restrict viral spread. Furthermore, basal expression levels of key interferon-stimulated genes are high in astrocytes compared to mouse embryonic fibroblasts. Bioinformatic analysis of RNA-sequencing data reveals that astrocytes have established a basal antiviral state which contributes to the rapid viral recognition and upregulation of interferons. The most highly upregulated pathways in neighboring cells were linked to type I interferon response and innate immunity. The restriction in viral growth was dependent on interferon signaling, since loss of the interferon receptor, or its blockade in wild-type cells, resulted in high viral replication and virus-induced cytopathic effects. Astrocyte supernatant from TBEV-infected cells can restrict TBEV growth in astrocytes already 6 h post infection, the effect on neurons is highly reinforced, and astrocyte supernatant from 3 h post infection is already protective. Conclusions: These findings suggest that the combination of an intrinsic constitutive antiviral response and the fast induction of type I IFN production by astrocytes play an important role in self-protection of astrocytes and suppression of flavivirus replication in the CNS.

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  • 36. Lumsden, A
    et al.
    Andreae, L
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lowell, S
    Schubert, F
    Hamann, S
    Reber, P J
    Häusser, M
    Murthy, V N
    Wood, J N
    Bredt, D S
    Ashe, J
    Chafee, M
    Merchant, H
    Goodwin, S
    Kyriacou, B
    Kempermann, G
    Winkler, J
    Neurobiology.2001In: Current Opinion in Neurobiology, ISSN 0959-4388, E-ISSN 1873-6882, Vol. 11, no 3, p. 259-66Article, review/survey (Refereed)
  • 37.
    Lövheim, Hugo
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Reactivated herpes simplex infection increases the risk of Alzheimer's disease2015In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 6, p. 593-599Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous studies have suggested a link between herpes simplex virus (HSV) type 1 and the development of Alzheimer's disease (AD).

    METHODS: The present analysis included 3432 persons (53.9% women, mean age at inclusion 62.7 ± 14.4 years) with a mean follow-up time of 11.3 years. The number of incident AD cases was 245. Serum samples were analyzed for anti-HSV antibodies (immunoglobulin (Ig)G and IgM) by enzyme-linked immunosorbent assays.

    RESULTS: The presence of anti-HSV IgG antibodies was not associated with an increased risk for AD, controlled for age and sex (hazard ratio, HR, 0.993, P = .979). However, the presence of anti-HSV IgM at baseline was associated with an increased risk of developing AD (HR 1.959, P = .012).

    CONCLUSION: Positivity for anti-HSV IgM, a sign of reactivated infection, was found to almost double the risk for AD, whereas the presence of anti-HSV IgG antibodies did not affect the risk.

  • 38.
    Lövheim, Hugo
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Herpes simplex infection and the risk of Alzheimer's disease: a nested case-control study2015In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 6, p. 587-592Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Herpes simplex virus (HSV) is thought to play an etiological role in the development of Alzheimer's disease (AD).

    METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years) and 360 age- and sex-matched dementia-free controls, taken on average 9.6 years before AD diagnosis, were analyzed for anti-HSV antibodies (immunoglobulin G, IgG, and immunoglobulin M, IgM) by enzyme-linked immunosorbent assays.

    RESULTS: In the complete sample group, the presence of anti-HSV IgG and IgM antibodies did not increase the risk of AD significantly (odds ratio (OR) 1.636, P = .069 and OR 1.368, P = .299, respectively). In cases with 6.6 years or more between plasma sampling and AD diagnosis (n = 270), there was a significant association between presence of anti-HSV IgG antibodies and AD (OR 2.250, P = .019).

    CONCLUSION: Among persons with a follow-up time of 6.6 years or more, HSV infection was significantly associated with AD.

  • 39.
    Malla, Sandhya
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Kumari, Kanchan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Martinez Gamero, Carlos
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    García-Prieto, carlos A.
    Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain .
    Álvarez-Errico3, Damiana
    Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain .
    Stransky, Stephanie
    4Department of Biochemistry, Albert Einstein College of Medicine, 10461 Bronx, NY, USA.
    Caroli, Jonatan
    5Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
    Saiki, Paulina Avovome
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Lai, Weiyi
    State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
    Lyu, Cong
    6State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
    Mattevi, Andrea
    Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wang, Hailin
    State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
    Sidoli, Simone
    4Department of Biochemistry, Albert Einstein College of Medicine, 10461 Bronx, NY, USA.
    Esteller, Manel
    Centro de Investigacion Biomedica en Red Cancer (CIBERONC, 28029 Madrid, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain.
    Roman, Angel
    Department of Biochemistry, Molecular Biology and Genetics, University of Extremadura, Badajoz, 06071, Spain.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    The catalytic-independent function of LSD1 modulates the epigenetic landscape of mouse embryonic stem cellsManuscript (preprint) (Other academic)
  • 40.
    Marsili, Luca
    et al.
    James J. and Joan A. Gardner Center for Parkinson’s Disease and Movement Disorders, Department of Neurology, University of Cincinnati, OH, Cincinnati, United States.
    Davis, Jennie L.
    Valley Neuroscience Institute, University of Washington-Valley Medical Center, WA, Renton, United States.
    Espay, Alberto J.
    James J. and Joan A. Gardner Center for Parkinson’s Disease and Movement Disorders, Department of Neurology, University of Cincinnati, OH, Cincinnati, United States.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kauffman, Marcelo A.
    Consultorio Y Laboratorio de Neurogenética, Centro Universitario de Neurología José María Ramos Mejía, Buenos Aires, Argentina.
    Porollo, Aleksey
    Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, OH, Cincinnati, United States; Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, OH, Cincinnati, United States; Department of Pediatrics, University of Cincinnati, OH, Cincinnati, United States.
    SOD1-related cerebellar ataxia and motor neuron disease: Cp variant as functional modifier?2024In: Cerebellum, ISSN 1473-4222, E-ISSN 1473-4230, Vol. 23, p. 205-209Article in journal (Refereed)
    Abstract [en]

    We describe a novel superoxide dismutase (SOD1) mutation-associated clinical phenotype of cerebellar ataxia and motor neuron disease with a variant in the ceruloplasmin (Cp) gene, which may have possibly contributed to a multi-factorial phenotype, supported by genetic and protein structure analyses.

  • 41. Meyer, Martin P
    et al.
    Trimmer, James S
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Smith, Stephen J
    Characterization of zebrafish PSD-95 gene family members.2005In: Journal of Neurobiology, ISSN 0022-3034, E-ISSN 1097-4695, Vol. 63, no 2, p. 91-105Article in journal (Refereed)
    Abstract [en]

    The PSD-95 family of membrane- associated guanylate kinases (MAGUKs) are thought to act as molecular scaffolds that regulate the assembly and function of the multiprotein signaling complex found at the postsynaptic density of excitatory synapses. Genetic analysis of PSD-95 family members in the mammalian nervous system has so far been difficult, but the zebrafish is emerging as an ideal vertebrate system for studying the role of particular genes in the developing and mature nervous system. Here we describe the cloning of the zebrafish orthologs of PSD-95, PSD-93, and two isoforms of SAP-97. Using in situ hybridization analysis we show that these zebrafish MAGUKs have overlapping but distinct patterns of expression in the developing nervous system and craniofacial skeleton. Using a pan-MAGUK antibody we show that MAGUK proteins localize to neurons within the developing hindbrain, cerebellum, visual and olfactory systems, and to skin epithelial cells. In the olfactory and visual systems MAGUK proteins are expressed strongly in synaptic regions, and the onset of expression in these areas coincides with periods of synapse formation. These data are consistent with the idea that PSD-95 family members are involved in synapse assembly and function, and provide a platform for future functional studies in vivo in a highly tractable model organism.

  • 42.
    Muthu, Magesh
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Kumar, Ranjeet
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Khaja, Azharuddin Sajid Syed
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nordström, Anders
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism2019In: Cancers, ISSN 2072-6694, Vol. 11, no 12, article id 1945Article in journal (Refereed)
    Abstract [en]

    Glutamate-ammonia ligase (GLUL) is important for acid-base homeostasis, ammonia detoxification, cell signaling, and proliferation. Here, we reported that GLUL ablation conferred resistance to several anticancer drugs in specific cancer cell lines while leaving other cell lines non-resistant to the same drugs. To understand the biochemical mechanics supporting this drug resistance, we compared drug-resistant GLUL knockout (KO) A549 non-small-cell lung carcinoma (NSCLC) cells with non-resistant GLUL KO H1299 NSCLC cells and found that the resistant A549 cells, to a larger extent, depended on exogenous glucose for proliferation. As GLUL activity is linked to the tricarboxylic acid (TCA) cycle via reversed glutaminolysis, we probed carbon flux through both glycolysis and TCA pathways by means of 13C5 glutamine, 13C5 glutamate, and 13C6 glucose tracing. We observed increased labeling of malate and aspartate in A549 GLUL KO cells, whereas the non-resistant GLUL KO H1299 cells displayed decreased 13C-labeling. The malate and aspartate shuttle supported cellular NADH production and was associated with cellular metabolic fitness. Inhibition of the malate-aspartate shuttle with aminooxyacetic acid significantly impacted upon cell viability with an IC50 of 11.5 μM in resistant GLUL KO A549 cells compared to 28 μM in control A549 cells, linking resistance to the malate-aspartate shuttle. Additionally, rescuing GLUL expression in A549 KO cells increased drug sensitivity. We proposed a novel metabolic mechanism in cancer drug resistance where the increased capacity of the malate-aspartate shuttle increased metabolic fitness, thereby facilitating cancer cells to escape drug pressure.

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  • 43.
    Muthukrishnan, Uma
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Natarajan, Balasubramanian
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Mäger, Imre
    Levén May, Hanna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jones, Iwan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Corso, Giulia
    Nordin, Joel Z.
    Wiklander, Oscar
    Johansson, Henrik J.
    Lehtiö, Janne
    Hällbrink, Mattias
    Wood, Matthew J.
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rome, Sophie
    Pini, Adrian
    Andaloussi, Samir EL
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    The exosome membrane localization of histones is independent of DNA and upregulated in response to stressManuscript (preprint) (Other academic)
    Abstract [en]

    Extracellular histones contribute to many acute and chronic diseases but also populate the secretomes of healthy cells and biofluids. However, a secretory pathway for histones has not been described. Here we report that core and linker histones localize to multivesicular bodies and are secreted via exosomes. Histones are tightly associated with the exosome membrane, with N-terminal domains exposed, in a DNA-independent manner. Furthermore, rapid upregulation of exosomal histones occurs following heat stress, accompanied by enhanced vesicle secretion and a shift towards a population of smaller vesicles. Proteomic analyses identified the downregulation of endosomal sorting complex required for transport (ESCRT) complex as a possible mechanism underlying increased histone secretion.We show for the first time that membrane-associated histones are actively secreted from intact cells via the multivesicular body/exosomal pathway. We demonstrate a novel pathway for extracellular histone release that may have a role in both health and disease.

  • 44.
    Månberg, Anna
    et al.
    Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.
    Skene, Nathan
    Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom; United Kingdom Dementia Research Institute, London, United Kingdom.
    Sanders, Folkert
    Department of Clinical Neuroscience, Karolinska Institute, Centre for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Trusohamn, Marta
    Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Remnestål, Julia
    Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.
    Szczepińska, Anna
    Department of Clinical Neuroscience, Karolinska Institute, Centre for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Aksoylu, Inci Sevval
    Department of Clinical Neuroscience, Karolinska Institute, Centre for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Lönnerberg, Peter
    Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Ebarasi, Lwaki
    Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
    Wouters, Stefan
    Department of Clinical Neuroscience, Karolinska Institute, Centre for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Lehmann, Manuela
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Olofsson, Jennie
    Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.
    von Gohren Antequera, Inti
    Department of Clinical Neuroscience, Karolinska Institute, Centre for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Domaniku, Aylin
    Department of Clinical Neuroscience, Karolinska Institute, Centre for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    De Schaepdryver, Maxim
    Laboratory for Neurobiomarker Research, Department of Neurology, Leuven Brain Institute, KU Leuven (University of Leuven), Leuven, Belgium.
    De Vocht, Joke
    Neurology Department and Center for Brain & Disease Research, KU Leuven, VIB, Leuven, Belgium.
    Poesen, Koen
    Laboratory for Neurobiomarker Research, Department of Neurology, Leuven Brain Institute, KU Leuven (University of Leuven), Leuven, Belgium; Laboratory Medicine, UZ Leuven (University Hospital Leuven), Leuven, Belgium.
    Uhlén, Mathias
    Division of Systems Biology, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden; Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Anink, Jasper
    Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
    Mijnsbergen, Caroline
    Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
    Vergunst-Bosch, Hermieneke
    UMC Utrecht Brain Center, University Medical Center Utrecht, Department of Neurology, Utrecht University, Utrecht, Netherlands.
    Hübers, Annemarie
    University of Ulm, Neurology Clinic, Ulm, Germany; Division of Neurology, Geneva University Hospital, Geneva, Switzerland.
    Kläppe, Ulf
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Rodriguez-Vieitez, Elena
    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Hedlund, Eva
    Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Harris, Robert A.
    Department of Clinical Neuroscience, Karolinska Institute, Centre for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Aronica, Eleonora
    Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
    Van Damme, Philip
    Neurology Department and Center for Brain & Disease Research, KU Leuven, VIB, Leuven, Belgium.
    Ludolph, Albert
    University of Ulm, Neurology Clinic, Ulm, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ulm, Bonn, Germany.
    Veldink, Jan
    UMC Utrecht Brain Center, University Medical Center Utrecht, Department of Neurology, Utrecht University, Utrecht, Netherlands.
    Ingre, Caroline
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Nilsson, Peter
    Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.
    Lewandowski, Sebastian A.
    Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institute, Centre for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Altered perivascular fibroblast activity precedes ALS disease onset2021In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 27, no 4, p. 640-646Article in journal (Refereed)
    Abstract [en]

    Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.

  • 45.
    Najafi, Pardis
    et al.
    Department of Animal Sciences, Georg-August-University, Burckhardtweg 2, Göttingen, Germany; Center for Integrated Breeding Research, Georg-August-University, Albrecht-Thaer-Weg 3, Göttingen, Germany.
    Reimer, Christian
    Center for Integrated Breeding Research, Georg-August-University, Albrecht-Thaer-Weg 3, Göttingen, Germany; Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Höltystr. 10, Neustadt, Germany.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Jacobsen, Kirsten R.
    Ellegaard Göttingen Minipigs A/S, Sorø Landevej 302, Dalmose, Denmark.
    Ramløse, Maja
    Ellegaard Göttingen Minipigs A/S, Sorø Landevej 302, Dalmose, Denmark.
    Paul, Nora-Fabienne
    Department of Animal Sciences, Georg-August-University, Burckhardtweg 2, Göttingen, Germany.
    Simianer, Henner
    Department of Animal Sciences, Georg-August-University, Burckhardtweg 2, Göttingen, Germany; Center for Integrated Breeding Research, Georg-August-University, Albrecht-Thaer-Weg 3, Göttingen, Germany.
    Tetens, Jens
    Department of Animal Sciences, Georg-August-University, Burckhardtweg 2, Göttingen, Germany; Center for Integrated Breeding Research, Georg-August-University, Albrecht-Thaer-Weg 3, Göttingen, Germany.
    Falker-Gieske, Clemens
    Department of Animal Sciences, Georg-August-University, Burckhardtweg 2, Göttingen, Germany; Center for Integrated Breeding Research, Georg-August-University, Albrecht-Thaer-Weg 3, Göttingen, Germany.
    Genomic evidence for the suitability of Göttingen minipigs with a rare seizure phenotype as a model for human epilepsy2024In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753Article in journal (Refereed)
    Abstract [en]

    Epilepsy is a complex genetic disorder that affects about 2% of the global population. Although the frequency and severity of epileptic seizures can be reduced by a range of pharmacological interventions, there are no disease-modifying treatments for epilepsy. The development of new and more effective drugs is hindered by a lack of suitable animal models. Available rodent models may not recapitulate all key aspects of the disease. Spontaneous epileptic convulsions were observed in few Göttingen Minipigs (GMPs), which may provide a valuable alternative animal model for the characterisation of epilepsy-type diseases and for testing new treatments. We have characterised affected GMPs at the genome level and have taken advantage of primary fibroblast cultures to validate the functional impact of fixed genetic variants on the transcriptome level. We found numerous genes connected to calcium metabolism that have not been associated with epilepsy before, such as ADORA2B, CAMK1D, ITPKB, MCOLN2, MYLK, NFATC3, PDGFD, and PHKB. Our results have identified two transcription factor genes, EGR3 and HOXB6, as potential key regulators of CACNA1H, which was previously linked to epilepsy-type disorders in humans. Our findings provide the first set of conclusive results to support the use of affected subsets of GMPs as an alternative and more reliable model system to study human epilepsy. Further neurological and pharmacological validation of the suitability of GMPs as an epilepsy model is therefore warranted.

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  • 46.
    Nilsson, Lars
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Rahmani, Shapour
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hubert, Madlen
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Tuck, Simon
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    TAT-5 and TAT-6 P4-family ATPases regulate the release of extracellular vesicles containing polycystins from Caenorhabditis elegans sensillaManuscript (preprint) (Other academic)
  • 47. Nordin, Joel Z.
    et al.
    Lee, Yi
    Vader, Pieter
    Maeger, Imre
    Johansson, Henrik J.
    Heusermann, Wolf
    Wiklander, Oscar P. B.
    Hallbrink, Mattias
    Seow, Yiqi
    Bultema, Jarred J.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Davies, Tim
    Fairchild, Paul J.
    Gabrielsson, Susanne
    Meisner-Kober, Nicole C.
    Lehtio, Janne
    Smith, C. I. Edvard
    Wood, Matthew J. A.
    Andaloussi, Samir E. L.
    Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties2015In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 11, no 4, p. 879-883Article in journal (Refereed)
    Abstract [en]

    Extracellular vesicles (EVs) are natural nanoparticles that mediate intercellular transfer of RNA and proteins and are of great medical interest; serving as novel biomarkers and potential therapeutic agents. However, there is little consensus on the most appropriate method to isolate high-yield and high-purity EVs from various biological fluids. Here, we describe a systematic comparison between two protocols for EV purification: ultrafiltration with subsequent liquid chromatography (UF-LC) and differential ultracentrifugation (UC). A significantly higher EV yield resulted from UF-LC as compared to UC, without affecting vesicle protein composition. Importantly, we provide novel evidence that, in contrast to UC-purified EVs, the biophysical properties of UF-LC-purified EVs are preserved, leading toadifferent in vivo biodistribution, with less accumulation in lungs. Finally, we show that UF-LC is scalable and adaptable for EV isolation from complex media types such as stem cell media, which is of huge significance for future clinical applications involving EVs. 

  • 48.
    Panaliappan, Tamilarasan K.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Slekiene, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Jonasson, Anna-Karin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    CAM-Delam: an in vivo approach to visualize and quantify the delamination and invasion capacity of human cancer cells2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 10472Article in journal (Refereed)
    Abstract [en]

    The development of metastases is the major cause of cancer related death. To develop a standardized method that define the ability of human cancer cells to degrade the basement membrane, e.g. the delamination capacity, is of importance to assess metastatic aggressiveness. We now present the in vivo CAM-Delam assay to visualize and quantify the ability of human cancer cells to delaminate and invade. The method includes seeding cancer cells on the chick chorioallantoic membrane (CAM), followed by the evaluation of cancer-induced delamination and potential invasion within hours to a few days. By testing a range of human cancer cell lines in the CAM-Delam assay, our results show that the delamination capacity can be divided into four categories and used to quantify metastatic aggressiveness. Our results emphasize the usefulness of this assay for quantifying delamination capacity as a measurement of metastatic aggressiveness, and in unraveling the molecular mechanisms that regulate delamination, invasion, formation of micro-metastases and modulations of the tumor microenvironment. This method will be useful in both the preclinical and clinical characterization of tumor biopsies, and in the validation of compounds that may improve survival in metastatic cancer.

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  • 49.
    Pateras, Ioannis S.
    et al.
    2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gianniou, Despoina D.
    Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
    Margetis, Aggelos T.
    2nd Department of Internal Medicine, Athens Naval and Veterans Hospital, Athens, Greece.
    Avgeris, Margaritis
    Laboratory of Clinical Biochemistry-Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, “P. & A. Kyriakou” Children’s Hospital, Athens, Greece; Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
    Rousakis, Pantelis
    Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece.
    Legaki, Aigli-Ioanna
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Mirtschink, Peter
    Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
    Zhang, Wei
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Swedish Metabolomics Centre, Umeå University, Umeå, Sweden.
    Panoutsopoulou, Konstantina
    Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
    Delis, Anastasios D.
    Centre for Basic Research, Bioimaging Unit, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
    Pagakis, Stamatis N.
    Centre for Basic Research, Bioimaging Unit, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
    Tang, Wei
    Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), NCI, NIH, MD, Bethesda, United States; Data Science & Artificial Intelligence, R&D, AstraZeneca, MD, Gaithersburg, United States.
    Ambs, Stefan
    Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), NCI, NIH, MD, Bethesda, United States.
    Warpman Berglund, Ulrika
    Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Helleday, Thomas
    Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
    Varvarigou, Anastasia
    Department of Paediatrics, University of Patras Medical School, General University Hospital, Patras, Greece.
    Chatzigeorgiou, Antonios
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
    Nordström, Anders
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Swedish Metabolomics Centre, Umeå University, Umeå, Sweden.
    Tsitsilonis, Ourania E.
    Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece.
    Trougakos, Ioannis P.
    Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Frisan, Teresa
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming2023In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 21, no 1, article id 169Article in journal (Refereed)
    Abstract [en]

    Background: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.

    Methods: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model.

    Results: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model.

    Conclusions: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.

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  • 50.
    Pu, Longjun
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Wang, Jing
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lu, Qiongxuan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nilsson, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Philbrook, Alison
    Department of Biology, Brandeis University, Waltham, USA.
    Pandey, Anjali
    Department of Biology, Brandeis University, Waltham, USA.
    Zhao, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    van Schendel, Robin
    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    Koh, Alan
    MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK.
    Peres, Tanara V.
    MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK.
    Hashi, Weheliye H.
    MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK.
    Myint, Si Lhyam
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Brown, Andre
    MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK.
    Tijsterman, Marcel
    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    Sengupta, Piali
    Department of Biology, Brandeis University, Waltham, USA.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Integrated Science Lab (Icelab), Umeå University, Umeå, Sweden.
    Chen, Changchun
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in  C. elegans2023In: Nature Communications, E-ISSN 2041-1723, Vol. 14, article id 8410Article in journal (Refereed)
    Abstract [en]

    G protein-coupled receptors (GPCRs) mediate responses to various extracellular and intracellular cues. However, the large number of GPCR genes and their substantial functional redundancy make it challenging to systematically dissect GPCR functions in vivo. Here, we employ a CRISPR/Cas9-based approach, disrupting 1654 GPCR-encoding genes in 284 strains and mutating 152 neuropeptide-encoding genes in 38 strains in C. elegans. These two mutant libraries enable effective deorphanization of chemoreceptors, and characterization of receptors for neuropeptides in various cellular processes. Mutating a set of closely related GPCRs in a single strain permits the assignment of functions to GPCRs with functional redundancy. Our analyses identify a neuropeptide that interacts with three receptors in hypoxia-evoked locomotory responses, unveil a collection of regulators in pathogen-induced immune responses, and define receptors for the volatile food-related odorants. These results establish our GPCR and neuropeptide mutant libraries as valuable resources for the C. elegans community to expedite studies of GPCR signaling in multiple contexts.

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