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Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics
Machado–Joseph disease (MJD) or spinocerebellar ataxia 3 (SCA3) is a rare, inherited, monogenic, neurodegenerative disease, and the most common SCA worldwide. MJD/SCA3 causative mutation is an abnormal expansion of the triplet CAG at exon 10 within the ATXN3 gene. The gene encodes for ataxin-3, whic...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138583/ https://www.ncbi.nlm.nih.gov/pubmed/37108570 http://dx.doi.org/10.3390/ijms24087405 |
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author | Paulino, Rodrigo Nóbrega, Clévio |
author_facet | Paulino, Rodrigo Nóbrega, Clévio |
author_sort | Paulino, Rodrigo |
collection | PubMed |
description | Machado–Joseph disease (MJD) or spinocerebellar ataxia 3 (SCA3) is a rare, inherited, monogenic, neurodegenerative disease, and the most common SCA worldwide. MJD/SCA3 causative mutation is an abnormal expansion of the triplet CAG at exon 10 within the ATXN3 gene. The gene encodes for ataxin-3, which is a deubiquitinating protein that is also involved in transcriptional regulation. In normal conditions, the ataxin-3 protein polyglutamine stretch has between 13 and 49 glutamines. However, in MJD/SCA3 patients, the size of the stretch increases from 55 to 87, contributing to abnormal protein conformation, insolubility, and aggregation. The formation of aggregates, which is a hallmark of MJD/SCA3, compromises different cell pathways, leading to an impairment of cell clearance mechanisms, such as autophagy. MJD/SCA3 patients display several signals and symptoms in which the most prominent is ataxia. Neuropathologically, the regions most affected are the cerebellum and the pons. Currently, there are no disease-modifying therapies, and patients rely only on supportive and symptomatic treatments. Due to these facts, there is a huge research effort to develop therapeutic strategies for this incurable disease. This review aims to bring together current state-of-the-art strategies regarding the autophagy pathway in MJD/SCA3, focusing on evidence for its impairment in the disease context and, importantly, its targeting for the development of pharmacological and gene-based therapies. |
format | Online Article Text |
id | pubmed-10138583 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101385832023-04-28 Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics Paulino, Rodrigo Nóbrega, Clévio Int J Mol Sci Review Machado–Joseph disease (MJD) or spinocerebellar ataxia 3 (SCA3) is a rare, inherited, monogenic, neurodegenerative disease, and the most common SCA worldwide. MJD/SCA3 causative mutation is an abnormal expansion of the triplet CAG at exon 10 within the ATXN3 gene. The gene encodes for ataxin-3, which is a deubiquitinating protein that is also involved in transcriptional regulation. In normal conditions, the ataxin-3 protein polyglutamine stretch has between 13 and 49 glutamines. However, in MJD/SCA3 patients, the size of the stretch increases from 55 to 87, contributing to abnormal protein conformation, insolubility, and aggregation. The formation of aggregates, which is a hallmark of MJD/SCA3, compromises different cell pathways, leading to an impairment of cell clearance mechanisms, such as autophagy. MJD/SCA3 patients display several signals and symptoms in which the most prominent is ataxia. Neuropathologically, the regions most affected are the cerebellum and the pons. Currently, there are no disease-modifying therapies, and patients rely only on supportive and symptomatic treatments. Due to these facts, there is a huge research effort to develop therapeutic strategies for this incurable disease. This review aims to bring together current state-of-the-art strategies regarding the autophagy pathway in MJD/SCA3, focusing on evidence for its impairment in the disease context and, importantly, its targeting for the development of pharmacological and gene-based therapies. MDPI 2023-04-17 /pmc/articles/PMC10138583/ /pubmed/37108570 http://dx.doi.org/10.3390/ijms24087405 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Paulino, Rodrigo Nóbrega, Clévio Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics |
title | Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics |
title_full | Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics |
title_fullStr | Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics |
title_full_unstemmed | Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics |
title_short | Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics |
title_sort | autophagy in spinocerebellar ataxia type 3: from pathogenesis to therapeutics |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138583/ https://www.ncbi.nlm.nih.gov/pubmed/37108570 http://dx.doi.org/10.3390/ijms24087405 |
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