title: New links between SOD1 and metabolic dysfunction from a yeast model of amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Bastow
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Amber R
authors.initials: AR
authors.lastname: Peswani
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Daniel S J
authors.initials: DS
authors.lastname: Tarrant
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Pentland
authors.affiliation: Institute of Translational Medicine, Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Translational Medicine, Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Alan
authors.identifier: 0000-0002-0346-1289
authors.initials: A
authors.lastname: Morgan
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Staniforth
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Jennifer M
authors.identifier: 0000-0002-2037-526X
authors.initials: JM
authors.lastname: Tullet
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Rowe
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Howard
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK M.F.Tuite@kent.ac.uk C.W.Gourlay@kent.ac.uk.
authors.forename: Mick F
authors.identifier: 0000-0002-5214-540X
authors.initials: MF
authors.lastname: Tuite
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK M.F.Tuite@kent.ac.uk C.W.Gourlay@kent.ac.uk.
authors.forename: Campbell W
authors.identifier: 0000-0002-2373-6788
authors.initials: CW
authors.lastname: Gourlay
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000096:biosynthesis; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D055442:Metabolome; D050296:Microbial Viability; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D066329:Protein Aggregates; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000254:growth & development; D012995:Solubility; D013312:Stress, Physiological; D000072105:Superoxide Dismutase-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism
chemical_list: D000596:Amino Acids; D007527:Isoenzymes; D050505:Mutant Proteins; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; D000072105:Superoxide Dismutase-1
keywords: ALS; Metabolism; SOD1; Vacuole; Yeast