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Huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1

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 cytotoxicit...

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Autores principales: Meriin, Anatoli B., Zhang, Xiaoqian, He, Xiangwei, Newnam, Gary P., Chernoff, Yury O., Sherman, Michael Y.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174031/
https://www.ncbi.nlm.nih.gov/pubmed/12058016
http://dx.doi.org/10.1083/jcb.200112104
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author Meriin, Anatoli B.
Zhang, Xiaoqian
He, Xiangwei
Newnam, Gary P.
Chernoff, Yury O.
Sherman, Michael Y.
author_facet Meriin, Anatoli B.
Zhang, Xiaoqian
He, Xiangwei
Newnam, Gary P.
Chernoff, Yury O.
Sherman, Michael Y.
author_sort Meriin, Anatoli B.
collection PubMed
description 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.
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spelling pubmed-21740312008-05-01 Huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1 Meriin, Anatoli B. Zhang, Xiaoqian He, Xiangwei Newnam, Gary P. Chernoff, Yury O. Sherman, Michael Y. J Cell Biol Article 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. The Rockefeller University Press 2002-06-10 /pmc/articles/PMC2174031/ /pubmed/12058016 http://dx.doi.org/10.1083/jcb.200112104 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Meriin, Anatoli B.
Zhang, Xiaoqian
He, Xiangwei
Newnam, Gary P.
Chernoff, Yury O.
Sherman, Michael Y.
Huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1
title Huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1
title_full Huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1
title_fullStr Huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1
title_full_unstemmed Huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1
title_short Huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1
title_sort huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein rnq1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174031/
https://www.ncbi.nlm.nih.gov/pubmed/12058016
http://dx.doi.org/10.1083/jcb.200112104
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