Title:
Polyglutamine toxicity is controlled by prion composition and gene dosage in yeast
Polyglutamine toxicity is controlled by prion composition and gene dosage in yeast
Author(s)
Gong, He
Romanova, Nina V.
Allen, Kim D.
Chandramowlishwaran, Pavithra
Gokhale, Kavita
Newnam, Gary P.
Mieczkowski, Piotr
Sherman, Michael Y.
Chernoff, Yury O.
Romanova, Nina V.
Allen, Kim D.
Chandramowlishwaran, Pavithra
Gokhale, Kavita
Newnam, Gary P.
Mieczkowski, Piotr
Sherman, Michael Y.
Chernoff, Yury O.
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Abstract
Polyglutamine expansion causes diseases in humans and other mammals. One example is Huntington’s disease. Fragments
of human huntingtin protein having an expanded polyglutamine stretch form aggregates and cause cytotoxicity in yeast
cells bearing endogenous QN-rich proteins in the aggregated (prion) form. Attachment of the proline(P)-rich region targets
polyglutamines to the large perinuclear deposit (aggresome). Aggresome formation ameliorates polyglutamine cytotoxicity
in cells containing only the prion form of Rnq1 protein. Here we show that expanded polyglutamines both with (poly-QP) or
without (poly-Q) a P-rich stretch remain toxic in the presence of the prion form of translation termination (release) factor
Sup35 (eRF3). A Sup35 derivative that lacks the QN-rich domain and is unable to be incorporated into aggregates
counteracts cytotoxicity, suggesting that toxicity is due to Sup35 sequestration. Increase in the levels of another release
factor, Sup45 (eRF1), due to either disomy by chromosome II containing the SUP45 gene or to introduction of the SUP45-
bearing plasmid counteracts poly-Q or poly-QP toxicity in the presence of the Sup35 prion. Protein analysis confirms that
polyglutamines alter aggregation patterns of Sup35 and promote aggregation of Sup45, while excess Sup45 counteracts
these effects. Our data show that one and the same mode of polyglutamine aggregation could be cytoprotective or
cytotoxic, depending on the composition of other aggregates in a eukaryotic cell, and demonstrate that other aggregates
expand the range of proteins that are susceptible to sequestration by polyglutamines.
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Date Issued
2012-04-19
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