title: Using yeast models to probe the molecular basis of amyotrophic lateral sclerosis.
abstract: ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative disease attributable to the death of motor neurons. Associated with ALS are mutations in the genes encoding SOD1 (superoxide dismutase 1), FUS (fused in Sarcoma) protein and TDP-43 (TAR DNA-binding protein-43) each of which leads to aggregation of the respective protein. For example, the ALS-associated mutations in the hSOD1 (human SOD1) gene typically destabilize the native SOD homodimer, leading to misfolding, aggregation and degradation of SOD1. The ALS-associated pathology is not a consequence of the functional inactivation of SOD1 itself, but is rather due to a toxic gain-of-function triggered by mutant SOD1. Recently, the molecular basis of a number of human neurodegenerative diseases resulting from protein misfolding and aggregation, including fALS (familial ALS), was probed by using the baker's yeast, Saccharomyces cerevisiae, as a highly tractable model. Such studies have, for example, identified novel mutant SOD1-specific interactions and demonstrated that mutant SOD1 disrupts mitochondrial homoeostasis. Features of ALS associated with TDP-43 aggregation have also been recapitulated in S. cerevisiae including the identification of modulators of the toxicity of TDP-43. In this paper, we review recent studies of ALS pathogenesis using S. cerevisiae as a model organism and summarize the potential mechanisms involved in ALS progression.
authors.affiliation: School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Bastow
authors.forename: Campbell W
authors.initials: CW
authors.lastname: Gourlay
authors.forename: Mick F
authors.initials: MF
authors.lastname: Tuite
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000503:physiopathology* / Q000628:therapy; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018869:Heat-Shock Response / Q000502:physiology; D006801:Humans; D009154:Mutation; D017510:Protein Folding; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1