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¹ Boston University School of Medicine, Boston, MA 02118
² Massachusetts Institute of Technology, Cambridge, MA 02139
³ School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332

Address correspondence to M.Y. Sherman, Boston University School of Medicine, Dept. of Biochemistry, K323, 715 Albany St., Boston, MA 02118. Tel.: (617) 638-5971. Fax: (617) 638-5339. E-mail: sherman{at}biochem.bumc.bu.edu

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.

Key Words: aggregation; polyglutamine; toxicity; prions; yeast

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