Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1782286162747981824 |
---|---|
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. |
format | Online Article Text |
id | pubmed-3787372 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT xuqiaoqiao synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms AT huangshanshan synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms AT songmingke synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms AT wangchuanen synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms AT yansen synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms AT liuxudong synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms AT gaertigmartaa synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms AT yushanping synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms AT lihe synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms AT lishihua synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms AT lixiaojiang synapticmutanthuntingtininhibitssynapsin1phosphorylationandcausesneurologicalsymptoms |