title: Distinct mechanisms of mutant huntingtin toxicity in different yeast strains.
abstract: Expansion of polyglutamine stretches in several proteins causes neurodegenerative amyloidoses, including Huntington disease. In yeast, mutant huntingtin (mHtt) with a stretch of 103 glutamine residues (HttQ103) forms toxic aggregates. A range of yeast strains have been used to elucidate the mechanisms of mHtt toxicity, and have revealed perturbations of various unrelated processes. HttQ103 aggregates can induce aggregation of cellular proteins, many of which contain glutamine/asparagine-rich regions, including Sup35 and Def1. In the strain 74-D694 HttQ103, toxicity is related to aggregation-mediated depletion of soluble Sup35 and its interacting partner Sup45. Def1 was also implicated in mHtt toxicity, since its lack detoxified HttQ103 in another yeast strain, BY4741. Here we show that in BY4742, deletion of DEF1 lowers HttQ103 toxicity and decreases the amount of its polymers, but does not affect copolymerization of Sup35. Furthermore, in contrast to 74-D694, increasing the levels of soluble Sup35 and Sup45 does not alleviate toxicity of HttQ103 in BY4742. These data demonstrate a difference in the mechanisms underlying mHtt toxicity in different yeast strains and suggest that in humans with Huntington disease, neurons of different brain compartments and cells in other tissues can also be damaged by different mechanisms.
authors.affiliation: Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia.
authors.forename: Genrikh V
authors.initials: GV
authors.lastname: Serpionov
authors.affiliation: Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Alexandrov
authors.affiliation: Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia mdter@inbi.ras.ru.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ter-Avanesyan
mesh_terms: D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein / Q000633:toxicity*; D050505:Mutant Proteins / Q000633:toxicity; D010454:Peptide Termination Factors / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015003:Yeasts / Q000187:drug effects*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C451742:DEF1 protein, S cerevisiae; C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D010454:Peptide Termination Factors; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins
keywords: Sup35/eRF3; Sup45/eRF1; amyloid cross-seeding; huntingtin toxicity; polyglutamine; yeast