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Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology

Expansion of polyglutamine (polyQ) tract may cause protein misfolding and aggregation that lead to cytotoxicity and neurodegeneration, but the underlying mechanism remains to be elucidated. We applied ataxin-3 (Atx3), a polyQ tract-containing protein, as a model to study sequestration of normal cell...

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Autores principales: Yang, Hui, Li, Jing-Jing, Liu, Shuai, Zhao, Jian, Jiang, Ya-Jun, Song, Ai-Xin, Hu, Hong-Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377324/
https://www.ncbi.nlm.nih.gov/pubmed/25231079
http://dx.doi.org/10.1038/srep06410
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author Yang, Hui
Li, Jing-Jing
Liu, Shuai
Zhao, Jian
Jiang, Ya-Jun
Song, Ai-Xin
Hu, Hong-Yu
author_facet Yang, Hui
Li, Jing-Jing
Liu, Shuai
Zhao, Jian
Jiang, Ya-Jun
Song, Ai-Xin
Hu, Hong-Yu
author_sort Yang, Hui
collection PubMed
description Expansion of polyglutamine (polyQ) tract may cause protein misfolding and aggregation that lead to cytotoxicity and neurodegeneration, but the underlying mechanism remains to be elucidated. We applied ataxin-3 (Atx3), a polyQ tract-containing protein, as a model to study sequestration of normal cellular proteins. We found that the aggregates formed by polyQ-expanded Atx3 sequester its interacting partners, such as P97/VCP and ubiquitin conjugates, into the protein inclusions through specific interactions both in vitro and in cells. Moreover, this specific sequestration impairs the normal cellular function of P97 in down-regulating neddylation. However, expansion of polyQ tract in Atx3 does not alter the conformation of its surrounding regions and the interaction affinities with the interacting partners, although it indeed facilitates misfolding and aggregation of the Atx3 protein. Thus, we propose a loss-of-function pathology for polyQ diseases that sequestration of the cellular essential proteins via specific interactions into inclusions by the polyQ aggregates causes dysfunction of the corresponding proteins, and consequently leads to neurodegeneration.
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spelling pubmed-53773242017-04-05 Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology Yang, Hui Li, Jing-Jing Liu, Shuai Zhao, Jian Jiang, Ya-Jun Song, Ai-Xin Hu, Hong-Yu Sci Rep Article Expansion of polyglutamine (polyQ) tract may cause protein misfolding and aggregation that lead to cytotoxicity and neurodegeneration, but the underlying mechanism remains to be elucidated. We applied ataxin-3 (Atx3), a polyQ tract-containing protein, as a model to study sequestration of normal cellular proteins. We found that the aggregates formed by polyQ-expanded Atx3 sequester its interacting partners, such as P97/VCP and ubiquitin conjugates, into the protein inclusions through specific interactions both in vitro and in cells. Moreover, this specific sequestration impairs the normal cellular function of P97 in down-regulating neddylation. However, expansion of polyQ tract in Atx3 does not alter the conformation of its surrounding regions and the interaction affinities with the interacting partners, although it indeed facilitates misfolding and aggregation of the Atx3 protein. Thus, we propose a loss-of-function pathology for polyQ diseases that sequestration of the cellular essential proteins via specific interactions into inclusions by the polyQ aggregates causes dysfunction of the corresponding proteins, and consequently leads to neurodegeneration. Nature Publishing Group 2014-09-18 /pmc/articles/PMC5377324/ /pubmed/25231079 http://dx.doi.org/10.1038/srep06410 Text en Copyright © 2014, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 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 in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Article
Yang, Hui
Li, Jing-Jing
Liu, Shuai
Zhao, Jian
Jiang, Ya-Jun
Song, Ai-Xin
Hu, Hong-Yu
Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology
title Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology
title_full Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology
title_fullStr Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology
title_full_unstemmed Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology
title_short Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology
title_sort aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: implication in a loss-of-function pathology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377324/
https://www.ncbi.nlm.nih.gov/pubmed/25231079
http://dx.doi.org/10.1038/srep06410
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