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Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms

Many genetic mouse models of Huntington’s disease (HD) have established that mutant huntingtin (htt) accumulates in various subcellular regions to affect a variety of cellular functions, but whether and how synaptic mutant htt directly mediates HD neuropathology remains to be determined. We generate...

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Autores principales: Xu, Qiaoqiao, Huang, Shanshan, Song, Mingke, Wang, Chuan-En, Yan, Sen, Liu, Xudong, Gaertig, Marta A., Yu, Shan Ping, Li, He, Li, Shihua, Li, Xiao-Jiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787372/
https://www.ncbi.nlm.nih.gov/pubmed/24081492
http://dx.doi.org/10.1083/jcb.201303146
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author Xu, Qiaoqiao
Huang, Shanshan
Song, Mingke
Wang, Chuan-En
Yan, Sen
Liu, Xudong
Gaertig, Marta A.
Yu, Shan Ping
Li, He
Li, Shihua
Li, Xiao-Jiang
author_facet Xu, Qiaoqiao
Huang, Shanshan
Song, Mingke
Wang, Chuan-En
Yan, Sen
Liu, Xudong
Gaertig, Marta A.
Yu, Shan Ping
Li, He
Li, Shihua
Li, Xiao-Jiang
author_sort Xu, Qiaoqiao
collection PubMed
description Many genetic mouse models of Huntington’s disease (HD) have established that mutant huntingtin (htt) accumulates in various subcellular regions to affect a variety of cellular functions, but whether and how synaptic mutant htt directly mediates HD neuropathology remains to be determined. We generated transgenic mice that selectively express mutant htt in the presynaptic terminals. Although it was not overexpressed, synaptic mutant htt caused age-dependent neurological symptoms and early death in mice as well as defects in synaptic neurotransmitter release. Mass spectrometry analysis of synaptic fractions and immunoprecipitation of synapsin-1 from HD CAG150 knockin mouse brains revealed that mutant htt binds to synapsin-1, a protein whose phosphorylation is critical for neurotransmitter release. We found that polyglutamine-expanded exon1 htt binds to the C-terminal region of synapsin-1 to reduce synapsin-1 phosphorylation. Our findings point to a critical role for synaptic htt in the neurological symptoms of HD, providing a new therapeutic target.
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spelling pubmed-37873722014-03-30 Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms Xu, Qiaoqiao Huang, Shanshan Song, Mingke Wang, Chuan-En Yan, Sen Liu, Xudong Gaertig, Marta A. Yu, Shan Ping Li, He Li, Shihua Li, Xiao-Jiang J Cell Biol Research Articles Many genetic mouse models of Huntington’s disease (HD) have established that mutant huntingtin (htt) accumulates in various subcellular regions to affect a variety of cellular functions, but whether and how synaptic mutant htt directly mediates HD neuropathology remains to be determined. We generated transgenic mice that selectively express mutant htt in the presynaptic terminals. Although it was not overexpressed, synaptic mutant htt caused age-dependent neurological symptoms and early death in mice as well as defects in synaptic neurotransmitter release. Mass spectrometry analysis of synaptic fractions and immunoprecipitation of synapsin-1 from HD CAG150 knockin mouse brains revealed that mutant htt binds to synapsin-1, a protein whose phosphorylation is critical for neurotransmitter release. We found that polyglutamine-expanded exon1 htt binds to the C-terminal region of synapsin-1 to reduce synapsin-1 phosphorylation. Our findings point to a critical role for synaptic htt in the neurological symptoms of HD, providing a new therapeutic target. The Rockefeller University Press 2013-09-30 /pmc/articles/PMC3787372/ /pubmed/24081492 http://dx.doi.org/10.1083/jcb.201303146 Text en © 2013 Xu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Xu, Qiaoqiao
Huang, Shanshan
Song, Mingke
Wang, Chuan-En
Yan, Sen
Liu, Xudong
Gaertig, Marta A.
Yu, Shan Ping
Li, He
Li, Shihua
Li, Xiao-Jiang
Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms
title Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms
title_full Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms
title_fullStr Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms
title_full_unstemmed Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms
title_short Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms
title_sort synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787372/
https://www.ncbi.nlm.nih.gov/pubmed/24081492
http://dx.doi.org/10.1083/jcb.201303146
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