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Article: Expanded polyglutamine domain possesses nuclear export activity which modulates subcellular localization and toxicity of polyQ disease protein via exportin-1

TitleExpanded polyglutamine domain possesses nuclear export activity which modulates subcellular localization and toxicity of polyQ disease protein via exportin-1
Authors
Issue Date2011
Citation
Human Molecular Genetics, 2011, v. 20, n. 9, p. 1738-1750 How to Cite?
AbstractPolyglutamine (polyQ) diseases are a group of late-onset, progressive neurodegenerative disorders caused by CAG trinucleotide repeat expansion in the coding region of disease genes. The cell nucleus is an important site of pathology in polyQ diseases, and transcriptional dysregulation is one of the pathologic hallmarks observed. In this study, we showed that exportin-1 (Xpo1) regulates the nucleocytoplasmic distribution of expanded polyQ protein. We found that expanded polyQ protein, but not its unexpanded form, possesses nuclear export activity and interacts with Xpo1. Genetic manipulation of Xpo1 expression levels in transgenic Drosophila models of polyQ disease confirmed the specific nuclear export role of Xpo1 on expanded polyQ protein. Upon Xpo1 knockdown, the expanded polyQ protein was retained in the nucleus. The nuclear disease protein enhanced polyQ toxicity by binding to heat shock protein (hsp) gene promoter and abolished hsp gene induction. Further, we uncovered a developmental decline of Xpo1 protein levels in vivo that contributes to the accumulation of expanded polyQ protein in the nucleus of symptomatic polyQ transgenic mice. Taken together, we first showed that Xpo1 is a nuclear export receptor for expanded polyQ domain, and our findings establish a direct link between protein nuclear export and the progressive nature of polyQ neurodegeneration. © The Author 2011. Published by Oxford University Press. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/336092
ISSN
2023 Impact Factor: 3.1
2023 SCImago Journal Rankings: 1.602
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChan, Wing Man-
dc.contributor.authorTsoi, Ho-
dc.contributor.authorWu, Chi Chung-
dc.contributor.authorWong, Chi Hang-
dc.contributor.authorCheng, Tat Cheung-
dc.contributor.authorLi, Hoi Yeung-
dc.contributor.authorLau, Kwok Fai-
dc.contributor.authorShaw, Pang Chui-
dc.contributor.authorPerrimon, Norbert-
dc.contributor.authorChan, Ho Yin Edwin-
dc.date.accessioned2024-01-15T08:23:22Z-
dc.date.available2024-01-15T08:23:22Z-
dc.date.issued2011-
dc.identifier.citationHuman Molecular Genetics, 2011, v. 20, n. 9, p. 1738-1750-
dc.identifier.issn0964-6906-
dc.identifier.urihttp://hdl.handle.net/10722/336092-
dc.description.abstractPolyglutamine (polyQ) diseases are a group of late-onset, progressive neurodegenerative disorders caused by CAG trinucleotide repeat expansion in the coding region of disease genes. The cell nucleus is an important site of pathology in polyQ diseases, and transcriptional dysregulation is one of the pathologic hallmarks observed. In this study, we showed that exportin-1 (Xpo1) regulates the nucleocytoplasmic distribution of expanded polyQ protein. We found that expanded polyQ protein, but not its unexpanded form, possesses nuclear export activity and interacts with Xpo1. Genetic manipulation of Xpo1 expression levels in transgenic Drosophila models of polyQ disease confirmed the specific nuclear export role of Xpo1 on expanded polyQ protein. Upon Xpo1 knockdown, the expanded polyQ protein was retained in the nucleus. The nuclear disease protein enhanced polyQ toxicity by binding to heat shock protein (hsp) gene promoter and abolished hsp gene induction. Further, we uncovered a developmental decline of Xpo1 protein levels in vivo that contributes to the accumulation of expanded polyQ protein in the nucleus of symptomatic polyQ transgenic mice. Taken together, we first showed that Xpo1 is a nuclear export receptor for expanded polyQ domain, and our findings establish a direct link between protein nuclear export and the progressive nature of polyQ neurodegeneration. © The Author 2011. Published by Oxford University Press. All rights reserved.-
dc.languageeng-
dc.relation.ispartofHuman Molecular Genetics-
dc.titleExpanded polyglutamine domain possesses nuclear export activity which modulates subcellular localization and toxicity of polyQ disease protein via exportin-1-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1093/hmg/ddr049-
dc.identifier.pmid21300695-
dc.identifier.scopuseid_2-s2.0-79954464577-
dc.identifier.volume20-
dc.identifier.issue9-
dc.identifier.spage1738-
dc.identifier.epage1750-
dc.identifier.eissn1460-2083-
dc.identifier.isiWOS:000289311400007-

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