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School of Biological Sciences

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Author: Allen, Kim D. × End date: 2019 × Start date: 2000 × search.filters.applied.f.isOrgUnitOfPublicationTitle: College of Sciences ×

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Polyglutamine toxicity is controlled by prion composition and gene dosage in yeast

2012-04-19 , Gong, He , Romanova, Nina V. , Allen, Kim D. , Chandramowlishwaran, Pavithra , Gokhale, Kavita , Newnam, Gary P. , Mieczkowski, Piotr , Sherman, Michael Y. , Chernoff, Yury O.

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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An investigation of the genetic control of protein mutability : the role of the ubiquitin system in protein based inheritance in Saccharomyces Cerevisiae

2003-05 , Allen, Kim D.

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