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MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy
Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in th...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881766/ https://www.ncbi.nlm.nih.gov/pubmed/26755334 http://dx.doi.org/10.1038/mt.2016.13 |
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author | Pourshafie, Naemeh Lee, Philip R Chen, Ke-lian Harmison, George G Bott, Laura C Katsuno, Masahisa Sobue, Gen Burnett, Barrington G Fischbeck, Kenneth H Rinaldi, Carlo |
author_facet | Pourshafie, Naemeh Lee, Philip R Chen, Ke-lian Harmison, George G Bott, Laura C Katsuno, Masahisa Sobue, Gen Burnett, Barrington G Fischbeck, Kenneth H Rinaldi, Carlo |
author_sort | Pourshafie, Naemeh |
collection | PubMed |
description | Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3'-untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins. |
format | Online Article Text |
id | pubmed-4881766 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-48817662016-06-06 MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy Pourshafie, Naemeh Lee, Philip R Chen, Ke-lian Harmison, George G Bott, Laura C Katsuno, Masahisa Sobue, Gen Burnett, Barrington G Fischbeck, Kenneth H Rinaldi, Carlo Mol Ther Original Article Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3'-untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins. Nature Publishing Group 2016-05 2016-02-09 /pmc/articles/PMC4881766/ /pubmed/26755334 http://dx.doi.org/10.1038/mt.2016.13 Text en Copyright © 2016 Official journal of the American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Original Article Pourshafie, Naemeh Lee, Philip R Chen, Ke-lian Harmison, George G Bott, Laura C Katsuno, Masahisa Sobue, Gen Burnett, Barrington G Fischbeck, Kenneth H Rinaldi, Carlo MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy |
title | MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy |
title_full | MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy |
title_fullStr | MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy |
title_full_unstemmed | MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy |
title_short | MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy |
title_sort | mir-298 counteracts mutant androgen receptor toxicity in spinal and bulbar muscular atrophy |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881766/ https://www.ncbi.nlm.nih.gov/pubmed/26755334 http://dx.doi.org/10.1038/mt.2016.13 |
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