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  • 1.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hempel, Maja
    Santer, René
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Tsiakas, Konstantinos
    Johannsen, Jessika
    Volk, Alexander E.
    Bierhals, Tatjana
    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.
    Phenotype in an Infant with SOD1 Homozygous Truncating Mutation2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, no 5, p. 486-488Article in journal (Refereed)
  • 2.
    Ezer, Shlomit
    et al.
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
    Daana, Muhannad
    Child Development Centers, Clalit Health Care Services, Israel.
    Park, Julien H.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Department of General Pediatrics, University of Münster, Münster, Germany.
    Yanovsky-Dagan, Shira
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel.
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Basal, Adily
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel.
    Edvardson, Simon
    Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Pediatric Neurology Unit, Hadassah Medical Organization, Jerusalem, Israel.
    Saada, Ann
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
    Otto, Markus
    Department of Neurology, University Clinic, Ulm, Germany; Department of Neurology, University Clinic, Halle (Saale), Germany.
    Meiner, Vardiella
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter Munch
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Harel, Tamar
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
    Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity2022In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 145, no 3, p. 872-878Article in journal (Refereed)
    Abstract [en]

    Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.

  • 3.
    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.))
  • 4. Freischmidt, Axel
    et al.
    Wieland, Thomas
    Richter, Benjamin
    Ruf, Wolfgang
    Schaeffer, Veronique
    Mueller, Kathrin
    Marroquin, Nicolai
    Nordin, Frida
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Huebers, Annemarie
    Weydt, Patrick
    Pinto, Susana
    Press, Rayomond
    Millecamps, Stephanie
    Molko, Nicolas
    Bernard, Emilien
    Desnuelle, Claude
    Soriani, Marie-Helene
    Dorst, Johannes
    Graf, Elisabeth
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Feiler, Marisa S.
    Putz, Stefan
    Boeckers, Tobias M.
    Meyer, Thomas
    Winkler, Andrea S.
    Winkelman, Juliane
    de Carvalho, Mamede
    Thal, Dietmar R.
    Otto, Markus
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Volk, Alexander E.
    Kursula, Petri
    Danzer, Karin M.
    Lichtner, Peter
    Dikic, Ivan
    Meitinger, Thomas
    Ludolph, Albert C.
    Strom, Tim M.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Weishaupt, Jochen H.
    Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia2015In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 18, no 5, p. 631-+Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

  • 5.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ekhtiari Bidhendi, Elaheh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Marklund, Matthew
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    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.
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice2021In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 9, no 1, article id 111Article in journal (Refereed)
    Abstract [en]

    The deposition of aggregated proteins is a common neuropathological denominator for neurodegenerative disorders. Experimental evidence suggests that disease propagation involves prion-like mechanisms that cause the spreading of template-directed aggregation of specific disease-associated proteins. In transgenic (Tg) mouse models of superoxide dismutase-1 (SOD1)-linked amyotrophic lateral sclerosis (ALS), inoculation of minute amounts of human SOD1 (hSOD1) aggregates into the spinal cord or peripheral nerves induces premature ALS-like disease and template-directed hSOD1 aggregation that spreads along the neuroaxis. This infectious nature of spreading pathogenic aggregates might have implications for the safety of laboratory and medical staff, recipients of donated blood or tissue, or possibly close relatives and caregivers. Here we investigate whether transmission of ALS-like disease is unique to the spinal cord and peripheral nerve inoculations or if hSOD1 aggregation might spread from the periphery into the central nervous system (CNS). We inoculated hSOD1 aggregate seeds into the peritoneal cavity, hindlimb skeletal muscle or spinal cord of adult Tg mice expressing mutant hSOD1. Although we used up to 8000 times higher dose—compared to the lowest dose transmitting disease in spinal cord inoculations—the peripheral inoculations did not transmit seeded aggregation to the CNS or premature ALS-like disease in hSOD1 Tg mice. Nor was any hSOD1 aggregation detected in the liver, kidney, skeletal muscle or sciatic nerve. To explore potential reasons for the lack of disease transmission, we examined the stability of hSOD1 aggregates and found them to be highly vulnerable to both proteases and detergent. Our findings suggest that exposed individuals and personnel handling samples from ALS patients are at low risk of any potential transmission of seeded hSOD1 aggregation.

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  • 6.
    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)
  • 7.
    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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  • 8. Kurowska, Zuzanna
    et al.
    Jewett, Michael
    Brattås, Per Ludvik
    Jimenez-Ferrer, Itzia
    Kenez, Xuyian
    Björklund, Tomas
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brundin, Patrik
    Swanberg, Maria
    Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson's Disease2016In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, article id 31701Article in journal (Refereed)
    Abstract [en]

    Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD.

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  • 9.
    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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  • 10.
    Nordström, Ulrika
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Edlund, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Progressive induction of caudal neural character by graded Wnt signaling2002In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 5, no 6, p. 525-532Article in journal (Refereed)
    Abstract [en]

    Early in differentiation, all neural cells have a rostral character. Only later do posteriorly positioned neural cells acquire characteristics of caudal forebrain, midbrain and hindbrain cells. Caudalization of neural tissue in the chick embryo apparently involves the convergent actions of (i) fibroblast growth factor (FGF) signaling and (ii) signaling from the caudal paraxial mesoderm, or 'PMC activity', which has not yet been defined molecularly. Here we report evidence that Wnt signaling underlies PMC activity, and show that Wnt signals act directly and in a graded manner on anterior neural cells to induce their progressive differentiation into caudal forebrain, midbrain and hindbrain cells.

  • 11.
    Nordström, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Lang, Lisa
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, Stockholm, Sweden.
    Ekhtiari Bidhendi, Elaheh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Oliveberg, Mikael
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, Stockholm, Sweden.
    Danielsson, Jens
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, Stockholm, Sweden.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Mutant SOD1 aggregates formed in vitro and in cultured cells are polymorphic and differ from those arising in the CNS2023In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 164, no 1, p. 77-93Article in journal (Refereed)
    Abstract [en]

    Mutations in the human Superoxide dismutase 1 (hSOD1) gene are well-established cause of the motor neuron disease ALS. Patients and transgenic (Tg) ALS model mice carrying mutant variants develop hSOD1 aggregates in the CNS. We have identified two hSOD1 aggregate strains, which both transmit spreading template-directed aggregation and premature fatal paralysis when inoculated into adult transgenic mice. This prion-like spread of aggregation could be a primary disease mechanism in SOD1-induced ALS. Human SOD1 aggregation has been studied extensively both in cultured cells and under various conditions in vitro. To determine how the structure of aggregates formed in these model systems related to disease-associated aggregates in the CNS, we used a binary epitope-mapping assay to examine aggregates of hSOD1 variants G93A, G85R, A4V, D90A, and G127X formed in vitro, in four different cell lines and in the CNS of Tg mice. We found considerable variability between replicate sets of in vitro-generated aggregates. In contrast, there was a high similarity between replicates of a given hSOD1 mutant in a given cell line, but pronounced variations between different hSOD1 mutants and different cell lines in both structures and amounts of aggregates formed. The aggregates formed in vitro or in cultured cells did not replicate the aggregate strains that arise in the CNS. Our findings suggest that the distinct aggregate morphologies in the CNS could result from a micro-environment with stringent quality control combined with second-order selection by spreading ability. Explorations of pathogenesis and development of therapeutics should be conducted in models that replicate aggregate structures forming in the CNS. (Figure presented.)

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  • 12.
    Park, Julien H.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Department of General Paediatrics, University of Münster, Münster, Germany.
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Tsiakas, Konstantinos
    Department of Paediatrics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
    Keskin, Isil
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elpers, Christiane
    Department of General Paediatrics, University of Münster, Münster, Germany.
    Mannil, Manoj
    Clinic for Radiology, University Hospital Münster, WWU University of Münster, Münster, Germany.
    Heller, Raoul
    Starship Children's Health, Auckland City Hospital, Auckland, New Zealand.
    Nolan, Melinda
    Starship Children's Health, Auckland City Hospital, Auckland, New Zealand.
    Alburaiky, Salam
    Starship Children's Health, Auckland City Hospital, Auckland, New Zealand.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hempel, Maja
    Department of Paediatrics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
    Schara-Schmidt, Ulrike
    Department of Paediatric Neurology, University Hospital Essen, Essen, Germany.
    Biskup, Saskia
    CeGAT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany.
    Steinacker, Petra
    Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
    Otto, Markus
    Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
    Weishaupt, Jochen
    Division for Neurodegenerative Diseases, Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
    Hahn, Andreas
    Department of Child Neurology, Justus Liebig University, Giessen, Germany.
    Santer, Rene
    Department of Paediatrics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
    Marquardt, Thorsten
    Department of General Paediatrics, University of Münster, Münster, Germany.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-12023In: Brain Communications, E-ISSN 2632-1297, Vol. 5, no 1, article id fcad017Article in journal (Refereed)
    Abstract [en]

    Superoxide dismutase-1 is a ubiquitously expressed antioxidant enzyme. Mutations in SOD1 can cause amyotrophic lateral sclerosis, probably via a toxic gain-of-function involving protein aggregation and prion-like mechanisms. Recently, homozygosity for loss-of-function mutations in SOD1 has been reported in patients presenting with infantile-onset motor neuron disease. We explored the bodily effects of superoxide dismutase-1 enzymatic deficiency in eight children homozygous for the p.C112Wfs∗11 truncating mutation. In addition to physical and imaging examinations, we collected blood, urine and skin fibroblast samples. We used a comprehensive panel of clinically established analyses to assess organ function and analysed oxidative stress markers, antioxidant compounds, and the characteristics of the mutant Superoxide dismutase-1. From around 8 months of age, all patients exhibited progressive signs of both upper and lower motor neuron dysfunction, cerebellar, brain stem, and frontal lobe atrophy and elevated plasma neurofilament concentration indicating ongoing axonal damage. The disease progression seemed to slow down over the following years. The p.C112Wfs∗11 gene product is unstable, rapidly degraded and no aggregates were found in fibroblast. Most laboratory tests indicated normal organ integrity and only a few modest deviations were found. The patients displayed anaemia with shortened survival of erythrocytes containing decreased levels of reduced glutathione. A variety of other antioxidants and oxidant damage markers were within normal range. In conclusion, non-neuronal organs in humans show a remarkable tolerance to absence of Superoxide dismutase-1 enzymatic activity. The study highlights the enigmatic specific vulnerability of the motor system to both gain-of-function mutations in SOD1 and loss of the enzyme as in the here depicted infantile superoxide dismutase-1 deficiency syndrome.

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  • 13.
    Paré, Bastien
    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.
    Beaudin, Marie
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Saikali, Stephan
    Julien, Jean-Pierre
    Gilthorpe, Jonathan D.
    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.
    Cashman, Neil R.
    Andersen, Peter M.
    Forsberg, Karin
    Dupre, Nicolas
    Gould, Peter
    Brannstrom, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gros-Louis, Francois
    Misfolded SOD1 pathology in sporadic Amyotrophic Lateral Sclerosis2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 14223Article in journal (Refereed)
    Abstract [en]

    Aggregation of mutant superoxide dismutase 1 (SOD1) is a pathological hallmark of a subset of familial ALS patients. However, the possible role of misfolded wild type SOD1 in human ALS is highly debated. To ascertain whether or not misfolded SOD1 is a common pathological feature in non-SOD1 ALS, we performed a blinded histological and biochemical analysis of post mortem brain and spinal cord tissues from 19 sporadic ALS, compared with a SOD1 A4V patient as well as Alzheimer's disease (AD) and non-neurological controls. Multiple conformation-or misfolded-specific antibodies for human SOD1 were compared. These were generated independently by different research groups and were compared using standardized conditions. Five different misSOD1 staining patterns were found consistently in tissue sections from SALS cases and the SOD1 A4V patient, but were essentially absent in AD and non-neurological controls. We have established clear experimental protocols and provide specific guidelines for working, with conformational/misfolded SOD1-specific antibodies. Adherence to these guidelines will aid in the comparison of the results of future studies and better interpretation of staining patterns. This blinded, standardized and unbiased approach provides further support for a possible pathological role of misSOD1 in SALS.

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  • 14. Ventorp, Filip
    et al.
    Bay-Richter, Cecilie
    Nagendra, Analise Sauro
    Janelidze, Shorena
    Sjödahl Matsson, Viktor
    Lipton, Jack
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Westrin, Åsa
    Brundin, Patrik
    Brundin, Lena
    Exendin-4 Treatment Improves LPS-Induced Depressive-Like Behavior Without Affecting ProInflammatory Cytokines2017In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 7, no 2, p. 263-273Article in journal (Refereed)
    Abstract [en]

    Background: Exendin-4 is a peptide agonist of the glucagon-like peptide-1 (GLP-1) receptor, currently in clinical trials as a potential disease-modifying therapy for Parkinson's disease. In light of this, it is important to understand potential modes of action of exendin-4 in the brain. Exendin-4 is neuroprotective and has been proposed to be directly anti-inflammatory, and that this is one way it reduces neurodegeneration. However, prior studies have focused on animal models involving both neurodegeneration and inflammation, therefore, it is also possible that the observed decreased inflammation is secondary to reduced neurodegeneration. Objective: To investigate whether exendin-4 directly reduces inflammation in the brain following an insult that involves neuroinflammation but not neurodegeneration, namely systemic administration of lipopolysaccharide (LPS). Methods: Rats were administered LPS systemically and were treated with either 0.5 mu g/kg exendin-4 or saline vehicle injections over 5 days. Behavior was evaluated with forced swim test. We assayed TNF-alpha and IL-1 beta levels in cerebrospinal fluid and cytokine mRNA expression in striatal, hippocampal and cortical tissues using qPCR. We determined brain monoamines using high-performance liquid chromatography. Finally, we isolated primary brain microglia from rats and measured cytokine production after exendin-4 treatment and LPS stimulation. Results: Exendin-4 treatment did not affect cytokine mRNA expression in brain, cytokine levels in cerebrospinal fluid or cytokine production from cultured microglia, although there was a trend towards increased striatal dopamine. Importantly, exendin-4 significantly prevented depressive-like behavior at 24 hours after LPS injection, indicating that the drug engaged a target in the brain. Depressive-like behavior was associated with altered dopamine turnover in the striatum. Conclusion: We did not detect any anti-inflammatory effects of exendin-4. In previous studies exploring the effects of exendin-4 on brain insults involving neurodegeneration, observations of reduced inflammation might have been secondary to mitigation of neuronal death. Our results indicate that the effects of exendin-4 on behavior may be due to effects on dopamine synthesis or metabolism.

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