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Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice

Huntington's disease (HD) is caused by the expansion of a polyglutamine tract in the N-terminal region of huntingtin (htt) and is characterized by selective neurodegeneration. In addition to forming nuclear aggregates, mutant htt accumulates in neuronal processes as well as synapses and affects...

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Autores principales: Wang, Jianjun, Wang, Chuan-En, Orr, Adam, Tydlacka, Suzanne, Li, Shi-Hua, Li, Xiao-Jiang
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290845/
https://www.ncbi.nlm.nih.gov/pubmed/18362179
http://dx.doi.org/10.1083/jcb.200709080
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author Wang, Jianjun
Wang, Chuan-En
Orr, Adam
Tydlacka, Suzanne
Li, Shi-Hua
Li, Xiao-Jiang
author_facet Wang, Jianjun
Wang, Chuan-En
Orr, Adam
Tydlacka, Suzanne
Li, Shi-Hua
Li, Xiao-Jiang
author_sort Wang, Jianjun
collection PubMed
description Huntington's disease (HD) is caused by the expansion of a polyglutamine tract in the N-terminal region of huntingtin (htt) and is characterized by selective neurodegeneration. In addition to forming nuclear aggregates, mutant htt accumulates in neuronal processes as well as synapses and affects synaptic function. However, the mechanism for the synaptic toxicity of mutant htt remains to be investigated. We targeted fluorescent reporters for the ubiquitin–proteasome system (UPS) to presynaptic or postsynaptic terminals of neurons. Using these reporters and biochemical assays of isolated synaptosomes, we found that mutant htt decreases synaptic UPS activity in cultured neurons and in HD mouse brains that express N-terminal or full-length mutant htt. Given that the UPS is a key regulator of synaptic plasticity and function, our findings offer insight into the selective neuronal dysfunction seen in HD and also establish a method to measure synaptic UPS activity in other neurological disease models.
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spelling pubmed-22908452008-09-24 Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice Wang, Jianjun Wang, Chuan-En Orr, Adam Tydlacka, Suzanne Li, Shi-Hua Li, Xiao-Jiang J Cell Biol Research Articles Huntington's disease (HD) is caused by the expansion of a polyglutamine tract in the N-terminal region of huntingtin (htt) and is characterized by selective neurodegeneration. In addition to forming nuclear aggregates, mutant htt accumulates in neuronal processes as well as synapses and affects synaptic function. However, the mechanism for the synaptic toxicity of mutant htt remains to be investigated. We targeted fluorescent reporters for the ubiquitin–proteasome system (UPS) to presynaptic or postsynaptic terminals of neurons. Using these reporters and biochemical assays of isolated synaptosomes, we found that mutant htt decreases synaptic UPS activity in cultured neurons and in HD mouse brains that express N-terminal or full-length mutant htt. Given that the UPS is a key regulator of synaptic plasticity and function, our findings offer insight into the selective neuronal dysfunction seen in HD and also establish a method to measure synaptic UPS activity in other neurological disease models. The Rockefeller University Press 2008-03-24 /pmc/articles/PMC2290845/ /pubmed/18362179 http://dx.doi.org/10.1083/jcb.200709080 Text en Copyright © 2008, The Rockefeller University Press 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 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Wang, Jianjun
Wang, Chuan-En
Orr, Adam
Tydlacka, Suzanne
Li, Shi-Hua
Li, Xiao-Jiang
Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice
title Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice
title_full Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice
title_fullStr Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice
title_full_unstemmed Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice
title_short Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice
title_sort impaired ubiquitin–proteasome system activity in the synapses of huntington's disease mice
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290845/
https://www.ncbi.nlm.nih.gov/pubmed/18362179
http://dx.doi.org/10.1083/jcb.200709080
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