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Article: Assessing a peptidylic inhibitor-based therapeutic approach that simultaneously suppresses polyglutamine RNA- And proteinmediated toxicities in patient cells and Drosophila

TitleAssessing a peptidylic inhibitor-based therapeutic approach that simultaneously suppresses polyglutamine RNA- And proteinmediated toxicities in patient cells and Drosophila
Authors
KeywordsExpanded-cag RNA
Expanded-polyq protein
Nucleolin
P3
Polyglutamine disease
Qbp1
Spinocerebellar ataxia
Issue Date2016
Citation
DMM Disease Models and Mechanisms, 2016, v. 9, n. 3, p. 321-334 How to Cite?
AbstractPolyglutamine (polyQ) diseases represent a group of progressive neurodegenerative disorders that are caused by abnormal expansion of CAG triplet nucleotides in disease genes. Recent evidence indicates that not only mutant polyQ proteins, but also their corresponding mutant RNAs, contribute to the pathogenesis of polyQ diseases. Here, we describe the identification of a 13-aminoacid peptide, P3, which binds directly and preferentially to long-CAG RNA within the pathogenic range. When administered to cell and Drosophila disease models, as well as to patient-derived fibroblasts, P3 inhibited expanded-CAG-RNA-induced nucleolar stress and suppressed neurotoxicity. We further examined the combined therapeutic effect of P3 and polyQ-binding peptide 1 (QBP1), a well-characterized polyQ protein toxicity inhibitor, on neurodegeneration. When P3 and QBP1 were co-administered to disease models, both RNA and protein toxicities were effectively mitigated, resulting in a notable improvement of neurotoxicity suppression compared with the P3 and QBP1 single-treatment controls. Our findings indicate that targeting toxic RNAs and/or simultaneous targeting of toxic RNAs and their corresponding proteins could open up a new therapeutic strategy for treating polyQ degeneration.
Persistent Identifierhttp://hdl.handle.net/10722/336149
ISSN
2023 Impact Factor: 4.0
2023 SCImago Journal Rankings: 1.361
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhang, Qian-
dc.contributor.authorTsoi, Ho-
dc.contributor.authorPeng, Shaohong-
dc.contributor.authorLi, Pan P.-
dc.contributor.authorLau, Kwok Fai-
dc.contributor.authorRudnicki, Dobrila D.-
dc.contributor.authorNgo, Jacky Chi Ki-
dc.contributor.authorChan, Ho Yin Edwin-
dc.date.accessioned2024-01-15T08:23:56Z-
dc.date.available2024-01-15T08:23:56Z-
dc.date.issued2016-
dc.identifier.citationDMM Disease Models and Mechanisms, 2016, v. 9, n. 3, p. 321-334-
dc.identifier.issn1754-8403-
dc.identifier.urihttp://hdl.handle.net/10722/336149-
dc.description.abstractPolyglutamine (polyQ) diseases represent a group of progressive neurodegenerative disorders that are caused by abnormal expansion of CAG triplet nucleotides in disease genes. Recent evidence indicates that not only mutant polyQ proteins, but also their corresponding mutant RNAs, contribute to the pathogenesis of polyQ diseases. Here, we describe the identification of a 13-aminoacid peptide, P3, which binds directly and preferentially to long-CAG RNA within the pathogenic range. When administered to cell and Drosophila disease models, as well as to patient-derived fibroblasts, P3 inhibited expanded-CAG-RNA-induced nucleolar stress and suppressed neurotoxicity. We further examined the combined therapeutic effect of P3 and polyQ-binding peptide 1 (QBP1), a well-characterized polyQ protein toxicity inhibitor, on neurodegeneration. When P3 and QBP1 were co-administered to disease models, both RNA and protein toxicities were effectively mitigated, resulting in a notable improvement of neurotoxicity suppression compared with the P3 and QBP1 single-treatment controls. Our findings indicate that targeting toxic RNAs and/or simultaneous targeting of toxic RNAs and their corresponding proteins could open up a new therapeutic strategy for treating polyQ degeneration.-
dc.languageeng-
dc.relation.ispartofDMM Disease Models and Mechanisms-
dc.subjectExpanded-cag RNA-
dc.subjectExpanded-polyq protein-
dc.subjectNucleolin-
dc.subjectP3-
dc.subjectPolyglutamine disease-
dc.subjectQbp1-
dc.subjectSpinocerebellar ataxia-
dc.titleAssessing a peptidylic inhibitor-based therapeutic approach that simultaneously suppresses polyglutamine RNA- And proteinmediated toxicities in patient cells and Drosophila-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1242/dmm.022350-
dc.identifier.pmid26839389-
dc.identifier.scopuseid_2-s2.0-84961707864-
dc.identifier.volume9-
dc.identifier.issue3-
dc.identifier.spage321-
dc.identifier.epage334-
dc.identifier.eissn1754-8411-
dc.identifier.isiWOS:000371439600010-

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