Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • René Günther - , Technische Universität Dresden, German Center for Neurodegenerative Diseases (Author)
  • Arun Pal - , Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Chloe Williams - , Umeå University (Author)
  • Vitaly L. Zimyanin - , Technische Universität Dresden, University of Virginia (Author)
  • Maria Liehr - , Technische Universität Dresden (Author)
  • Cläre von Neubeck - , German Cancer Research Center, Technische Universität Dresden, University of Duisburg-Essen, West German Proton Therapy Centre Essen (WPE) gGmbH (Author)
  • Mechthild Krause - , Department of Radiation Oncology, German Cancer Research Center, Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Mrudula G. Parab - , Technische Universität Dresden (Author)
  • Susanne Petri - , Hannover Medical School (Author)
  • Norman Kalmbach - , Hannover Medical School (Author)
  • Stefan L. Marklund - , Umeå University (Author)
  • Jared Sterneckert - , Chair of iPS Cells and Neurodegenerative Diseases (Author)
  • Peter Munch Andersen - , Umeå University (Author)
  • Florian Wegner - , Hannover Medical School (Author)
  • Jonathan D. Gilthorpe - , Umeå University (Author)
  • Andreas Hermann - , University of Rostock, German Center for Neurodegenerative Diseases (Author)

Abstract

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.

Details

Original languageEnglish
Article number1246
Number of pages27
JournalCells
Volume11
Issue number7
Publication statusPublished - 6 Apr 2022
Peer-reviewedYes

External IDs

Mendeley e1934d10-dcc8-375e-8b96-33374f8af6ad
WOS 000781321900001

Keywords

Keywords

  • ALS1, axonal trafficking, live cell imaging, mitochondria, SOD1, PROTEIN, ALS, NEURODEGENERATION, AMYOTROPHIC-LATERAL-SCLEROSIS, HOMOZYGOSITY, MOTOR-NEURON DEGENERATION, GENE, SUPEROXIDE-DISMUTASE MUTATIONS, NEUROPATHOLOGY, STRESS GRANULES