Assessing a peptidylic inhibitor- based therapeutic approach that simultaneously suppresses polyglutamine RNA- and protein-mediated toxicities in patient cells and Drosophila
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摘要Polyglutamine (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-amino-acid 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.
著者Zhang Q, Tsoi H, Peng SH, Li PP, Lau KF, Rudnicki DD, Ngo JCK, Chan HYE
期刊名稱Disease Models and Mechanisms
出版年份2016
月份3
日期1
卷號9
期次3
出版社COMPANY OF BIOLOGISTS LTD
頁次321 - 334
國際標準期刊號1754-8403
電子國際標準期刊號1754-8411
語言英式英語
關鍵詞Expanded-CAG RNA; Expanded-polyQ protein; Nucleolin; P3; Polyglutamine disease; QBP1; Spinocerebellar ataxia
Web of Science 學科類別Cell Biology; Pathology

上次更新時間 2020-25-09 於 00:29