New links between SOD1 and metabolic dysfunction from a yeast model of amyotrophic lateral sclerosis.
A number of genes have been linked to familial forms of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). Over 150 mutations within the gene encoding superoxide dismutase 1 (SOD1) have been implicated in ALS, but why such mutations lead to ALS-associated cellular dysfunction is unclear. In this study, we identify how ALS-linked SOD1 mutations lead to changes in the cellular health of the yeast Saccharomyces cerevisiae We find that it is not the accumulation of aggregates but the loss of Sod1 protein stability that drives cellular dysfunction. The toxic effect of Sod1 instability does not correlate with a loss of mitochondrial function or increased production of reactive oxygen species, but instead prevents acidification of the vacuole, perturbs metabolic regulation and promotes senescence. Central to the toxic gain-of-function seen with the SOD1 mutants examined was an inability to regulate amino acid biosynthesis. We also report that leucine supplementation results in an improvement in motor function in a Caenorhabditis elegans model of ALS. Our data suggest that metabolic dysfunction plays an important role in Sod1-mediated toxicity in both the yeast and worm models of ALS.
['Bastow|Emma L|EL|', 'Peswani|Amber R|AR|', 'Tarrant|Daniel S J|DS|', 'Pentland|Daniel R|DR|', 'Chen|Xi|X|', 'Morgan|Alan|A|0000-0002-0346-1289', 'Staniforth|Gemma L|GL|', 'Tullet|Jennifer M|JM|0000-0002-2037-526X', 'Rowe|Michelle L|ML|', 'Howard|Mark J|MJ|', 'Tuite|Mick F|MF|0000-0002-5214-540X', 'Gourlay|Campbell W|CW|0000-0002-2373-6788']
D000483:Alleles D000595:Amino Acid Sequence D000596:Amino Acids D000690:Amyotrophic Lateral Sclerosis D000818:Animals D017173:Caenorhabditis elegans D007527:Isoenzymes D009682:Magnetic Resonance Spectroscopy D055442:Metabolome D050296:Microbial Viability D008928:Mitochondria D008954:Models, Biological D009046:Motor Neurons D050505:Mutant Proteins D009154:Mutation D066329:Protein Aggregates D017382:Reactive Oxygen Species D012441:Saccharomyces cerevisiae D012995:Solubility D013312:Stress, Physiological D000072105:Superoxide Dismutase-1 D014617:Vacuoles
SOD1 Metabolism Yeast ALS Vacuole