title: Huntington toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1.
abstract: The cause of Huntington's disease is expansion of polyglutamine (polyQ) domain in huntingtin, which makes this protein both neurotoxic and aggregation prone. Here we developed the first yeast model, which establishes a direct link between aggregation of expanded polyQ domain and its cytotoxicity. Our data indicated that deficiencies in molecular chaperones Sis1 and Hsp104 inhibited seeding of polyQ aggregates, whereas ssa1, ssa2, and ydj1-151 mutations inhibited expansion of aggregates. The latter three mutants strongly suppressed the polyQ toxicity. Spontaneous mutants with suppressed aggregation appeared with high frequency, and in all of them the toxicity was relieved. Aggregation defects in these mutants and in sis1-85 were not complemented in the cross to the hsp104 mutant, demonstrating an unusual type of inheritance. Since Hsp104 is required for prion maintenance in yeast, this suggested a role for prions in polyQ aggregation and toxicity. We screened a set of deletions of nonessential genes coding for known prions and related proteins and found that deletion of the RNQ1 gene specifically suppressed aggregation and toxicity of polyQ. Curing of the prion form of Rnq1 from wild-type cells dramatically suppressed both aggregation and toxicity of polyQ. We concluded that aggregation of polyQ is critical for its toxicity and that Rnq1 in its prion conformation plays an essential role in polyQ aggregation leading to the toxicity.
authors.affiliation: Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Anatoli B
authors.initials: AB
authors.lastname: Meriin
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiangwei
authors.initials: X
authors.lastname: He
authors.forename: Gary P
authors.initials: GP
authors.lastname: Newnam
authors.forename: Yury O
authors.initials: YO
authors.lastname: Chernoff
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Sherman
mesh_terms: D003433:Crosses, Genetic; D003470:Culture Media; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005787:Gene Frequency; D005838:Genotype; D049452:Green Fluorescent Proteins; D006816:Huntington Disease / Q000235:genetics; D008164:Luminescent Proteins; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000633:toxicity*; D009687:Nuclear Proteins / Q000235:genetics / Q000633:toxicity*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010641:Phenotype; D011099:Polyglutamic Acid / Q000378:metabolism*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins; D012995:Solubility; D013489:Suppression, Genetic
chemical_list: D003470:Culture Media; D005656:Fungal Proteins; D008164:Luminescent Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011328:Prions; C404807:RNQ1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D049452:Green Fluorescent Proteins; D011099:Polyglutamic Acid