Misfolded SOD1 Accumulation and Mitochondrial Association Contribute to the Selective Vulnerability of Motor Neurons in Familial ALS: Correlation to Human Disease

Salah Abu-Hamad, Marcel F. Leyton-Jaimes, Jonathan Rosenblatt, Adrian Israelson

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, with a 10% genetic linkage, of which 20% of these cases may be attributed to mutations in superoxide dismutase (SOD1). Specific mutations in SOD1 have been associated with disease duration, which can be highly variable ranging from a life expectancy of 3 to beyond 10 years. SOD1 neurotoxicity has been attributed to aberrant accumulation of misfolded SOD1, which in its soluble form binds to intracellular organelles disrupting their function or forms insoluble toxic aggregates. To understand whether these biophysical properties of the mutant protein may influence disease onset and duration, we generated 19 point mutations in the SOD1 gene, based on available clinical data of disease onset and progression from patients. By overexpressing these mutants in motor-neuron-like NSC-34 cells, we demonstrate a variability in misfolding capacity between the different mutants with a correlation between the degree of protein misfolding and mutation severity. We also show a clear variation of the different SOD1 mutants to associate with mitochondrial-enriched fractions with a correlation between mutation severity and this association. In summary, these findings reveal a correlation between the accumulation of misfolded SOD1 species and their mitochondrial association with disease duration but not with disease onset, and they have implications for the potential therapeutic role of suppressing the accumulation of misfolded SOD1.

Original languageEnglish
Pages (from-to)2225-2234
Number of pages10
JournalACS Chemical Neuroscience
Volume8
Issue number10
DOIs
StatePublished - 18 Oct 2017

Keywords

  • ALS
  • Mutant SOD1
  • misfolded SOD1
  • mitochondrial dysfunction

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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