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 SOD1 gene 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 instead the loss of Sod1 stability that drives cellular dysfunction. The toxic effects of Sod1 instability does not correlate with a loss of mitochondrial function or increased ROS production, 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 of motor function in a C. 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.
- Received April 4, 2016.
- Accepted September 16, 2016.
- © 2016. Published by The Company of Biologists Ltd