title: A yeast model for polyalanine-expansion aggregation and toxicity.
abstract: Nine human disorders result from the toxic accumulation and aggregation of proteins with expansions in their endogenous polyalanine (polyA) tracts. Given the prevalence of polyA tracts in eukaryotic proteomes, we wanted to understand the generality of polyA-expansion cytotoxicity by using yeast as a model organism. In our initial case, we expanded the polyA tract within the native yeast poly(Adenine)-binding protein Pab1 from 8A to 13A, 15A, 17A, and 20A. These expansions resulted in increasing formation of Pab1 inclusions, insolubility, and cytotoxicity that correlated with the length of the polyA expansion. Pab1 binds mRNA as part of its normal function, and disrupting RNA binding or altering cytoplasmic mRNA levels suppressed the cytotoxicity of 17A-expanded Pab1, indicating a requisite role for mRNA in Pab1 polyA-expansion toxicity. Surprisingly, neither manipulation suppressed the cytotoxicity of 20A-expanded Pab1. Thus longer expansions may have a different mechanism for toxicity. We think that this difference underscores the potential need to examine the cytotoxic mechanisms of both long and short expansions in models of expansion disorders.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Konopka
authors.forename: Melissa N
authors.initials: MN
authors.lastname: Locke
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Gallagher
authors.forename: Ngan
authors.initials: N
authors.lastname: Pham
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hart
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Walker
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.forename: Richard G
authors.initials: RG
authors.lastname: Gardner
mesh_terms: D000595:Amino Acid Sequence; D002449:Cell Aggregation; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000378:metabolism; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D039122:Poly(A)-Binding Protein I / Q000737:chemistry / Q000378:metabolism; D020543:Proteome; D012319:RNA Polymerase II / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D010455:Peptides; D010750:Phosphoproteins; D039122:Poly(A)-Binding Protein I; D020543:Proteome; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; C019529:polyalanine; C097188:polyglutamine; D012319:RNA Polymerase II; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1