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Gilthorpe, Jonathan D.ORCID iD iconorcid.org/0000-0002-6884-4774
Alternative names
Publications (10 of 59) Show all publications
Najafi, P., Reimer, C., Gilthorpe, J. D., Jacobsen, K. R., Ramløse, M., Paul, N.-F., . . . Falker-Gieske, C. (2024). Genomic evidence for the suitability of Göttingen minipigs with a rare seizure phenotype as a model for human epilepsy. Neurogenetics
Open this publication in new window or tab >>Genomic evidence for the suitability of Göttingen minipigs with a rare seizure phenotype as a model for human epilepsy
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2024 (English)In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753Article in journal (Refereed) Epub ahead of print
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.

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
Epilepsy, Genomics, Göttingen Minipigs, Seizure, Transcriptomics, Voltage-gated calcium channel
National Category
Medical Genetics Neurology
Identifiers
urn:nbn:se:umu:diva-221647 (URN)10.1007/s10048-024-00750-2 (DOI)001169113600001 ()38383918 (PubMedID)2-s2.0-85185459842 (Scopus ID)
Available from: 2024-03-06 Created: 2024-03-06 Last updated: 2024-03-06
Marsili, L., Davis, J. L., Espay, A. J., Gilthorpe, J. D., Williams, C., Kauffman, M. A. & Porollo, A. (2024). SOD1-related cerebellar ataxia and motor neuron disease: Cp variant as functional modifier?. Cerebellum, 23, 205-209
Open this publication in new window or tab >>SOD1-related cerebellar ataxia and motor neuron disease: Cp variant as functional modifier?
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2024 (English)In: Cerebellum, ISSN 1473-4222, E-ISSN 1473-4230, Vol. 23, p. 205-209Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
Amyotrophic lateral sclerosis, Cerebellar ataxia, Ceruloplasmin, Neurodegeneration, SOD1
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-205011 (URN)10.1007/s12311-023-01527-3 (DOI)000932029400002 ()36757662 (PubMedID)2-s2.0-85147710255 (Scopus ID)
Available from: 2023-02-22 Created: 2023-02-22 Last updated: 2024-04-26Bibliographically approved
Tsioras, K., Smith, K. C., Edassery, S. L., Garjani, M., Li, Y., Williams, C., . . . Kiskinis, E. (2023). Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis. Cell Reports, 42(10), Article ID 113160.
Open this publication in new window or tab >>Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis
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2023 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 10, article id 113160Article in journal (Refereed) Published
Abstract [en]

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
ALS, amyotrophic lateral sclerosis, CP: Neuroscience, CP: Stem cell research, iPSCs, motor neurons, protein degradation, SILAC-based mass spectrometry, SOD1, ubiquitin, VCP/p97
National Category
Cell and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:umu:diva-215749 (URN)10.1016/j.celrep.2023.113160 (DOI)37776851 (PubMedID)2-s2.0-85174155270 (Scopus ID)
Funder
NIH (National Institutes of Health)Swedish Research Council, 2019-01634
Available from: 2023-11-02 Created: 2023-11-02 Last updated: 2024-01-17Bibliographically approved
Pu, L., Wang, J., Lu, Q., Nilsson, L., Philbrook, A., Pandey, A., . . . Chen, C. (2023). Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in  C. elegans. Nature Communications, 14, Article ID 8410.
Open this publication in new window or tab >>Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in  C. elegans
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, article id 8410Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-217489 (URN)10.1038/s41467-023-44177-z (DOI)38110404 (PubMedID)2-s2.0-85180225404 (Scopus ID)
Funder
Swedish Research Council, 2018-02914Swedish Research Council, 2021-06602Swedish Research Council, 2018-02216
Note

Originally included in thesis in manuscript form. 

Available from: 2023-12-05 Created: 2023-12-05 Last updated: 2024-01-05Bibliographically approved
Falker-Gieske, C., Paul, N.-F., Spourita, M., Gilthorpe, J. D., Gustmann, K. & Tetens, J. (2023). Resistance to chicken amyloid arthropathy is associated with a dysfunctional mutation in serum amyloid A. The FASEB Journal, 37(1), Article ID e22700.
Open this publication in new window or tab >>Resistance to chicken amyloid arthropathy is associated with a dysfunctional mutation in serum amyloid A
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2023 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 37, no 1, article id e22700Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
amyloidosis, avian amyloid arthropathy, genomics, next generation sequencing, protein aggregation, serum amyloid A, transcriptomics
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-202058 (URN)10.1096/fj.202200359RR (DOI)001003587500033 ()36515677 (PubMedID)2-s2.0-85144587913 (Scopus ID)
Available from: 2023-01-03 Created: 2023-01-03 Last updated: 2023-09-05Bibliographically approved
Pateras, I. S., Williams, C., Gianniou, D. D., Margetis, A. T., Avgeris, M., Rousakis, P., . . . Frisan, T. (2023). Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming. Journal of Translational Medicine, 21(1), Article ID 169.
Open this publication in new window or tab >>Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming
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2023 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 21, no 1, article id 169Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Breast cancer, Caloric restriction, Fasting, Metabolic reprogramming, Mitochondria, Oncological treatment, Oxidative stress, Reactive oxygen species, Starvation, Triple negative breast cancer
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-205797 (URN)10.1186/s12967-023-03935-9 (DOI)000943526300004 ()36869333 (PubMedID)2-s2.0-85149714467 (Scopus ID)
Funder
The Kempe Foundations, JCK-1526The Kempe Foundations, KCK-1620Swedish Research Council, 2021-00960Swedish Cancer Society, 2017/315The Kempe Foundations, JCK-1826Cancerforskningsfonden i Norrland, AMP20-993Cancerforskningsfonden i Norrland, AMP 17-884
Available from: 2023-03-28 Created: 2023-03-28 Last updated: 2023-03-28Bibliographically approved
Günther, R., Pal, A., Williams, C., Zimyanin, V. L., Liehr, M., von Neubeck, C., . . . Hermann, A. (2022). Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS. Cells, 11(7), Article ID 1246.
Open this publication in new window or tab >>Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS
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2022 (English)In: Cells, E-ISSN 2073-4409, Vol. 11, no 7, article id 1246Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
ALS1, axonal trafficking, live cell imaging, mitochondria, SOD1
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-193795 (URN)10.3390/cells11071246 (DOI)000781321900001 ()35406813 (PubMedID)2-s2.0-85127602913 (Scopus ID)
Funder
Swedish Research Council, VR-MH 2019-01634
Available from: 2022-05-06 Created: 2022-05-06 Last updated: 2023-03-24Bibliographically approved
Leppert, A., Chen, G., Lianoudaki, D., Williams, C., Zhong, X., Gilthorpe, J. D., . . . Johansson, J. (2022). ATP-independent molecular chaperone activity generated under reducing conditions. Protein Science, 31(8), Article ID e4378.
Open this publication in new window or tab >>ATP-independent molecular chaperone activity generated under reducing conditions
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2022 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 31, no 8, article id e4378Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
ATP-independent molecular chaperone, Bri2 BRICHOS, BRICHOS domain, disulfide bond formation, extracellular protein aggregation
National Category
Biochemistry and Molecular Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-198486 (URN)10.1002/pro.4378 (DOI)000823698600001 ()35900025 (PubMedID)2-s2.0-85135199147 (Scopus ID)
Funder
Åhlén-stiftelsenSwedish Cancer SocietyGun och Bertil Stohnes StiftelseMagnus Bergvall FoundationOlle Engkvists stiftelseHedlund foundationStiftelsen Gamla TjänarinnorStiftelsen Sigurd och Elsa Goljes minneAlzheimerfondenSwedish Foundation for Strategic ResearchSwedish Research Council, 2016-01967Swedish Research Council, 2019-01634Swedish Research Council, 2019-01961
Available from: 2022-08-11 Created: 2022-08-11 Last updated: 2022-08-11Bibliographically approved
Román, S., Stahel, A., Gilthorpe, J. D., Eddebo, J. & Lundström, N. (2022). Serious side effects exceed the risk of hospitalization with COVID-19 in the Swedish population.
Open this publication in new window or tab >>Serious side effects exceed the risk of hospitalization with COVID-19 in the Swedish population
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2022 (English)Other (Refereed)
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-203205 (URN)
Note

Published 2022-07-15

Available from: 2023-01-16 Created: 2023-01-16 Last updated: 2023-01-16Bibliographically approved
Månberg, A., Skene, N., Sanders, F., Trusohamn, M., Remnestål, J., Szczepińska, A., . . . Lewandowski, S. A. (2021). Altered perivascular fibroblast activity precedes ALS disease onset [Letter to the editor]. Nature Medicine, 27(4), 640-646
Open this publication in new window or tab >>Altered perivascular fibroblast activity precedes ALS disease onset
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2021 (English)In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 27, no 4, p. 640-646Article in journal, Letter (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-182762 (URN)10.1038/s41591-021-01295-9 (DOI)000640612600022 ()2-s2.0-85104433969 (Scopus ID)
Note

Publisher Correction:Månberg, A., Skene, N., Sanders, F. et al. Publisher Correction: Altered perivascular fibroblast activity precedes ALS disease onset. Nat Med 27, 1308 (2021). DOI: 10.1038/s41591-021-01414-6

Available from: 2021-05-11 Created: 2021-05-11 Last updated: 2023-09-05Bibliographically approved
Projects
Understanding disease mechanisms in neurodegeneration using patient-derived cell models of ALS [2019-01634_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6884-4774

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