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The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models

Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is obser...

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Autores principales: Hsu, Jung-Yu, Jhang, Yu-Ling, Cheng, Pei-Hsun, Chang, Yu-Fan, Mao, Su-Han, Yang, Han-In, Lin, Chia-Wei, Chen, Chuan-Mu, Yang, Shang-Hsun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476786/
https://www.ncbi.nlm.nih.gov/pubmed/28676741
http://dx.doi.org/10.3389/fnmol.2017.00196
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author Hsu, Jung-Yu
Jhang, Yu-Ling
Cheng, Pei-Hsun
Chang, Yu-Fan
Mao, Su-Han
Yang, Han-In
Lin, Chia-Wei
Chen, Chuan-Mu
Yang, Shang-Hsun
author_facet Hsu, Jung-Yu
Jhang, Yu-Ling
Cheng, Pei-Hsun
Chang, Yu-Fan
Mao, Su-Han
Yang, Han-In
Lin, Chia-Wei
Chen, Chuan-Mu
Yang, Shang-Hsun
author_sort Hsu, Jung-Yu
collection PubMed
description Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is observed to cause neuronal death in SCA3 patients. Based on previous studies, proteolytic cleavage of mutant ATXN3 is found to produce truncated C-terminal fragments in SCA3 models. However, whether these truncated mutant fragments disturb mitochondrial functions and result in pathological death is still unclear. Here, we used neuroblastoma cell and transgenic mouse models to examine the effects of truncated mutant ATXN3 on mitochondria functions. In different models, we observed truncated mutant ATXN3 accelerated the formation of aggregates, which translocated into the nucleus to form intranuclear aggregates. In addition, truncated mutant ATXN3 caused more mitochondrial fission, and decreased the expression of mitochondrial fusion markers, including Mfn-1 and Mfn-2. Furthermore, truncated mutant ATXN3 decreased the mitochondrial membrane potential, increased reactive oxygen species and finally increased cell death rate. In transgenic mouse models, truncated mutant ATXN3 also led to more mitochondrial dysfunction, neurodegeneration and cell death in the cerebellums. This study supports the toxic fragment hypothesis in SCA3, and also provides evidence that truncated mutant ATXN3 is severer than full-length mutant one in vitro and in vivo.
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spelling pubmed-54767862017-07-04 The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models Hsu, Jung-Yu Jhang, Yu-Ling Cheng, Pei-Hsun Chang, Yu-Fan Mao, Su-Han Yang, Han-In Lin, Chia-Wei Chen, Chuan-Mu Yang, Shang-Hsun Front Mol Neurosci Neuroscience Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is observed to cause neuronal death in SCA3 patients. Based on previous studies, proteolytic cleavage of mutant ATXN3 is found to produce truncated C-terminal fragments in SCA3 models. However, whether these truncated mutant fragments disturb mitochondrial functions and result in pathological death is still unclear. Here, we used neuroblastoma cell and transgenic mouse models to examine the effects of truncated mutant ATXN3 on mitochondria functions. In different models, we observed truncated mutant ATXN3 accelerated the formation of aggregates, which translocated into the nucleus to form intranuclear aggregates. In addition, truncated mutant ATXN3 caused more mitochondrial fission, and decreased the expression of mitochondrial fusion markers, including Mfn-1 and Mfn-2. Furthermore, truncated mutant ATXN3 decreased the mitochondrial membrane potential, increased reactive oxygen species and finally increased cell death rate. In transgenic mouse models, truncated mutant ATXN3 also led to more mitochondrial dysfunction, neurodegeneration and cell death in the cerebellums. This study supports the toxic fragment hypothesis in SCA3, and also provides evidence that truncated mutant ATXN3 is severer than full-length mutant one in vitro and in vivo. Frontiers Media S.A. 2017-06-20 /pmc/articles/PMC5476786/ /pubmed/28676741 http://dx.doi.org/10.3389/fnmol.2017.00196 Text en Copyright © 2017 Hsu, Jhang, Cheng, Chang, Mao, Yang, Lin, Chen and Yang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Hsu, Jung-Yu
Jhang, Yu-Ling
Cheng, Pei-Hsun
Chang, Yu-Fan
Mao, Su-Han
Yang, Han-In
Lin, Chia-Wei
Chen, Chuan-Mu
Yang, Shang-Hsun
The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models
title The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models
title_full The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models
title_fullStr The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models
title_full_unstemmed The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models
title_short The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models
title_sort truncated c-terminal fragment of mutant atxn3 disrupts mitochondria dynamics in spinocerebellar ataxia type 3 models
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476786/
https://www.ncbi.nlm.nih.gov/pubmed/28676741
http://dx.doi.org/10.3389/fnmol.2017.00196
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