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Ataxin-3 Protein and RNA Toxicity in Spinocerebellar Ataxia Type 3: Current Insights and Emerging Therapeutic Strategies
Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines,...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012159/ https://www.ncbi.nlm.nih.gov/pubmed/24293103 http://dx.doi.org/10.1007/s12035-013-8596-2 |
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author | Evers, Melvin M. Toonen, Lodewijk J. A. van Roon-Mom, Willeke M. C. |
author_facet | Evers, Melvin M. Toonen, Lodewijk J. A. van Roon-Mom, Willeke M. C. |
author_sort | Evers, Melvin M. |
collection | PubMed |
description | Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3). In spite of extensive research, the molecular mechanisms underlying the cellular toxicity resulting from mutant ataxin-3 remain elusive and no preventive treatment is currently available. It has become clear over the last decade that the hallmark intracellular ataxin-3 aggregates are likely not the main toxic entity in SCA3. Instead, the soluble PolyQ containing fragments arising from proteolytic cleavage of ataxin-3 by caspases and calpains are now regarded to be of greater influence in pathogenesis. In addition, recent evidence suggests potential involvement of a RNA toxicity component in SCA3 and other PolyQ expansion disorders, increasing the pathogenic complexity. Herein, we review the functioning of ataxin-3 and the involvement of known protein and RNA toxicity mechanisms of mutant ataxin-3 that have been discovered, as well as future opportunities for therapeutic intervention. |
format | Online Article Text |
id | pubmed-4012159 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-40121592014-05-07 Ataxin-3 Protein and RNA Toxicity in Spinocerebellar Ataxia Type 3: Current Insights and Emerging Therapeutic Strategies Evers, Melvin M. Toonen, Lodewijk J. A. van Roon-Mom, Willeke M. C. Mol Neurobiol Article Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3). In spite of extensive research, the molecular mechanisms underlying the cellular toxicity resulting from mutant ataxin-3 remain elusive and no preventive treatment is currently available. It has become clear over the last decade that the hallmark intracellular ataxin-3 aggregates are likely not the main toxic entity in SCA3. Instead, the soluble PolyQ containing fragments arising from proteolytic cleavage of ataxin-3 by caspases and calpains are now regarded to be of greater influence in pathogenesis. In addition, recent evidence suggests potential involvement of a RNA toxicity component in SCA3 and other PolyQ expansion disorders, increasing the pathogenic complexity. Herein, we review the functioning of ataxin-3 and the involvement of known protein and RNA toxicity mechanisms of mutant ataxin-3 that have been discovered, as well as future opportunities for therapeutic intervention. Springer US 2013-11-29 2014 /pmc/articles/PMC4012159/ /pubmed/24293103 http://dx.doi.org/10.1007/s12035-013-8596-2 Text en © The Author(s) 2013 https://creativecommons.org/licenses/by/2.0/ Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Article Evers, Melvin M. Toonen, Lodewijk J. A. van Roon-Mom, Willeke M. C. Ataxin-3 Protein and RNA Toxicity in Spinocerebellar Ataxia Type 3: Current Insights and Emerging Therapeutic Strategies |
title | Ataxin-3 Protein and RNA Toxicity in Spinocerebellar Ataxia Type 3: Current Insights and Emerging Therapeutic Strategies |
title_full | Ataxin-3 Protein and RNA Toxicity in Spinocerebellar Ataxia Type 3: Current Insights and Emerging Therapeutic Strategies |
title_fullStr | Ataxin-3 Protein and RNA Toxicity in Spinocerebellar Ataxia Type 3: Current Insights and Emerging Therapeutic Strategies |
title_full_unstemmed | Ataxin-3 Protein and RNA Toxicity in Spinocerebellar Ataxia Type 3: Current Insights and Emerging Therapeutic Strategies |
title_short | Ataxin-3 Protein and RNA Toxicity in Spinocerebellar Ataxia Type 3: Current Insights and Emerging Therapeutic Strategies |
title_sort | ataxin-3 protein and rna toxicity in spinocerebellar ataxia type 3: current insights and emerging therapeutic strategies |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012159/ https://www.ncbi.nlm.nih.gov/pubmed/24293103 http://dx.doi.org/10.1007/s12035-013-8596-2 |
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