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Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS
Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Dresden, Germany.
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.
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
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.
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2022 (Engelska)Ingår i: Cells, E-ISSN 2073-4409, Vol. 11, nr 7, artikel-id 1246Artikel i tidskrift (Refereegranskat) 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.

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MDPI, 2022. Vol. 11, nr 7, artikel-id 1246
Nyckelord [en]
ALS1, axonal trafficking, live cell imaging, mitochondria, SOD1
Nationell ämneskategori
Neurologi
Identifikatorer
URN: urn:nbn:se:umu:diva-193795DOI: 10.3390/cells11071246ISI: 000781321900001PubMedID: 35406813Scopus ID: 2-s2.0-85127602913OAI: oai:DiVA.org:umu-193795DiVA, id: diva2:1656623
Forskningsfinansiär
Vetenskapsrådet, VR-MH 2019-01634Tillgänglig från: 2022-05-06 Skapad: 2022-05-06 Senast uppdaterad: 2023-03-24Bibliografiskt granskad

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Williams, ChloeMarklund, Stefan L.Andersen, Peter M.Gilthorpe, Jonathan D.

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