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A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases
Polyglutamine (polyQ) diseases are a class of progressive neurodegenerative disorders characterized by the expression of both expanded CAG RNA and misfolded polyQ protein. We previously reported that the direct interaction between expanded CAG RNA and nucleolar protein nucleolin (NCL) impedes prerib...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855950/ https://www.ncbi.nlm.nih.gov/pubmed/29295891 http://dx.doi.org/10.1261/rna.062703.117 |
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author | Zhang, Qian Chen, Zhefan Stephen An, Ying Liu, Haizhen Hou, Yonghui Li, Wen Lau, Kwok-Fai Koon, Alex Chun Ngo, Jacky Chi Ki Chan, Ho Yin Edwin |
author_facet | Zhang, Qian Chen, Zhefan Stephen An, Ying Liu, Haizhen Hou, Yonghui Li, Wen Lau, Kwok-Fai Koon, Alex Chun Ngo, Jacky Chi Ki Chan, Ho Yin Edwin |
author_sort | Zhang, Qian |
collection | PubMed |
description | Polyglutamine (polyQ) diseases are a class of progressive neurodegenerative disorders characterized by the expression of both expanded CAG RNA and misfolded polyQ protein. We previously reported that the direct interaction between expanded CAG RNA and nucleolar protein nucleolin (NCL) impedes preribosomal RNA (pre-rRNA) transcription, and eventually triggers nucleolar stress-induced apoptosis in polyQ diseases. Here, we report that a 21-amino acid peptide, named “beta-structured inhibitor for neurodegenerative diseases” (BIND), effectively suppresses toxicity induced by expanded CAG RNA. When administered to a cell model, BIND potently inhibited cell death induced by expanded CAG RNA with an IC(50) value of ∼0.7 µM. We showed that the function of BIND is dependent on Glu2, Lys13, Gly14, Ile18, Glu19, and Phe20. BIND treatment restored the subcellular localization of nucleolar marker protein and the expression level of pre-45s rRNA. Through isothermal titration calorimetry analysis, we demonstrated that BIND suppresses nucleolar stress via a direct interaction with CAG RNA in a length-dependent manner. The mean binding constants (K(D)) of BIND to SCA2(CAG22), SCA2(CAG42), SCA2(CAG55), and SCA2(CAG72) RNA are 17.28, 5.60, 4.83, and 0.66 µM, respectively. In vivo, BIND ameliorates retinal degeneration and climbing defects, and extends the lifespan of Drosophila expressing expanded CAG RNA. These effects suggested that BIND can suppress neurodegeneration in diverse polyQ disease models in vivo and in vitro without exerting observable cytotoxic effect. Our results collectively demonstrated that BIND is an effective inhibitor of expanded CAG RNA-induced toxicity in polyQ diseases. |
format | Online Article Text |
id | pubmed-5855950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58559502019-04-01 A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases Zhang, Qian Chen, Zhefan Stephen An, Ying Liu, Haizhen Hou, Yonghui Li, Wen Lau, Kwok-Fai Koon, Alex Chun Ngo, Jacky Chi Ki Chan, Ho Yin Edwin RNA Article Polyglutamine (polyQ) diseases are a class of progressive neurodegenerative disorders characterized by the expression of both expanded CAG RNA and misfolded polyQ protein. We previously reported that the direct interaction between expanded CAG RNA and nucleolar protein nucleolin (NCL) impedes preribosomal RNA (pre-rRNA) transcription, and eventually triggers nucleolar stress-induced apoptosis in polyQ diseases. Here, we report that a 21-amino acid peptide, named “beta-structured inhibitor for neurodegenerative diseases” (BIND), effectively suppresses toxicity induced by expanded CAG RNA. When administered to a cell model, BIND potently inhibited cell death induced by expanded CAG RNA with an IC(50) value of ∼0.7 µM. We showed that the function of BIND is dependent on Glu2, Lys13, Gly14, Ile18, Glu19, and Phe20. BIND treatment restored the subcellular localization of nucleolar marker protein and the expression level of pre-45s rRNA. Through isothermal titration calorimetry analysis, we demonstrated that BIND suppresses nucleolar stress via a direct interaction with CAG RNA in a length-dependent manner. The mean binding constants (K(D)) of BIND to SCA2(CAG22), SCA2(CAG42), SCA2(CAG55), and SCA2(CAG72) RNA are 17.28, 5.60, 4.83, and 0.66 µM, respectively. In vivo, BIND ameliorates retinal degeneration and climbing defects, and extends the lifespan of Drosophila expressing expanded CAG RNA. These effects suggested that BIND can suppress neurodegeneration in diverse polyQ disease models in vivo and in vitro without exerting observable cytotoxic effect. Our results collectively demonstrated that BIND is an effective inhibitor of expanded CAG RNA-induced toxicity in polyQ diseases. Cold Spring Harbor Laboratory Press 2018-04 /pmc/articles/PMC5855950/ /pubmed/29295891 http://dx.doi.org/10.1261/rna.062703.117 Text en © 2018 Zhang et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Article Zhang, Qian Chen, Zhefan Stephen An, Ying Liu, Haizhen Hou, Yonghui Li, Wen Lau, Kwok-Fai Koon, Alex Chun Ngo, Jacky Chi Ki Chan, Ho Yin Edwin A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases |
title | A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases |
title_full | A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases |
title_fullStr | A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases |
title_full_unstemmed | A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases |
title_short | A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases |
title_sort | peptidylic inhibitor for neutralizing expanded cag rna-induced nucleolar stress in polyglutamine diseases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855950/ https://www.ncbi.nlm.nih.gov/pubmed/29295891 http://dx.doi.org/10.1261/rna.062703.117 |
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