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Article: CAG expansion induces nucleolar stress in polyglutamine diseases

TitleCAG expansion induces nucleolar stress in polyglutamine diseases
Authors
KeywordsDrosophila
Machado-Joseph disease
Rna toxicity
Spinocerebellar ataxia
Issue Date2012
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2012, v. 109, n. 33, p. 13428-13433 How to Cite?
AbstractThe cell nucleus is amajor site for polyglutamine (polyQ) toxicity, but the underlying mechanisms involved have yet been fully elucidated. Here, we report that mutant RNAs that carry an expanded CAG repeat (expanded CAG RNAs) induce apoptosis by activating the nucleolar stress pathway in both polyQ patients and transgenic animal disease models. We showed that expanded CAG RNAs interacted directly with nucleolin (NCL), a protein that regulates rRNA transcription. Such RNA-protein interaction deprived NCL of binding to upstream control element (UCE) of the rRNA promoter, which resulted in UCE DNA hypermethylation and subsequently perturbation of rRNA transcription. The down-regulation of rRNA transcription induced nucleolar stress and provoked apoptosis by promoting physical interaction between ribosomal proteins and MDM2. Consequently, p53 protein was found to be stabilized in cells and became concentrated in the mitochondria. Finally, we showed that mitochondrial p53 disrupted the interaction between the antiapoptotic protein, Bcl-xL, and the proapoptotic protein, Bak, which then caused cytochrome c release and caspase activation. Our work provides in vivo evidence that expanded CAG RNAs trigger nucleolar stress and induce apoptosis via p53 and describes a polyQ pathogenic mechanism that involves the nucleolus.
Persistent Identifierhttp://hdl.handle.net/10722/336105
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTsoi, Ho-
dc.contributor.authorLau, Terrence Chi Kong-
dc.contributor.authorTsang, Suk Ying-
dc.contributor.authorLau, Kwok Fai-
dc.contributor.authorChan, Ho Yin Edwin-
dc.date.accessioned2024-01-15T08:23:30Z-
dc.date.available2024-01-15T08:23:30Z-
dc.date.issued2012-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2012, v. 109, n. 33, p. 13428-13433-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/336105-
dc.description.abstractThe cell nucleus is amajor site for polyglutamine (polyQ) toxicity, but the underlying mechanisms involved have yet been fully elucidated. Here, we report that mutant RNAs that carry an expanded CAG repeat (expanded CAG RNAs) induce apoptosis by activating the nucleolar stress pathway in both polyQ patients and transgenic animal disease models. We showed that expanded CAG RNAs interacted directly with nucleolin (NCL), a protein that regulates rRNA transcription. Such RNA-protein interaction deprived NCL of binding to upstream control element (UCE) of the rRNA promoter, which resulted in UCE DNA hypermethylation and subsequently perturbation of rRNA transcription. The down-regulation of rRNA transcription induced nucleolar stress and provoked apoptosis by promoting physical interaction between ribosomal proteins and MDM2. Consequently, p53 protein was found to be stabilized in cells and became concentrated in the mitochondria. Finally, we showed that mitochondrial p53 disrupted the interaction between the antiapoptotic protein, Bcl-xL, and the proapoptotic protein, Bak, which then caused cytochrome c release and caspase activation. Our work provides in vivo evidence that expanded CAG RNAs trigger nucleolar stress and induce apoptosis via p53 and describes a polyQ pathogenic mechanism that involves the nucleolus.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectDrosophila-
dc.subjectMachado-Joseph disease-
dc.subjectRna toxicity-
dc.subjectSpinocerebellar ataxia-
dc.titleCAG expansion induces nucleolar stress in polyglutamine diseases-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1073/pnas.1204089109-
dc.identifier.pmid22847428-
dc.identifier.scopuseid_2-s2.0-84865191445-
dc.identifier.volume109-
dc.identifier.issue33-
dc.identifier.spage13428-
dc.identifier.epage13433-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000307807000062-

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