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Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes
See Huang and Gitler (doi:10.1093/brain/awy112) for a scientific commentary on this article. Lowering the levels of disease-causing proteins is an attractive treatment strategy for neurodegenerative disorders, among which Huntington’s disease is an appealing disease for testing this strategy because...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972579/ https://www.ncbi.nlm.nih.gov/pubmed/29608652 http://dx.doi.org/10.1093/brain/awy081 |
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author | Song, Haikun Li, Hexuan Guo, Shimeng Pan, Yuyin Fu, Yuhua Zhou, Zijian Li, Zhaoyang Wen, Xue Sun, Xiaoli He, Bingqing Gu, Haifeng Zhao, Quan Wang, Cen An, Ping Luo, Shouqing Hu, Youhong Xie, Xin Lu, Boxun |
author_facet | Song, Haikun Li, Hexuan Guo, Shimeng Pan, Yuyin Fu, Yuhua Zhou, Zijian Li, Zhaoyang Wen, Xue Sun, Xiaoli He, Bingqing Gu, Haifeng Zhao, Quan Wang, Cen An, Ping Luo, Shouqing Hu, Youhong Xie, Xin Lu, Boxun |
author_sort | Song, Haikun |
collection | PubMed |
description | See Huang and Gitler (doi:10.1093/brain/awy112) for a scientific commentary on this article. Lowering the levels of disease-causing proteins is an attractive treatment strategy for neurodegenerative disorders, among which Huntington’s disease is an appealing disease for testing this strategy because of its monogenetic nature. Huntington’s disease is mainly caused by cytotoxicity of the mutant HTT protein with an expanded polyglutamine repeat tract. Lowering the soluble mutant HTT may reduce its downstream toxicity and provide potential treatment for Huntington’s disease. This is hard to achieve by small-molecule compound drugs because of a lack of effective targets. Here we demonstrate Gpr52, an orphan G protein-coupled receptor, as a potential Huntington’s disease drug target. Knocking-out Gpr52 significantly reduces mutant HTT levels in the striatum and rescues Huntington’s disease-associated behavioural phenotypes in a knock-in Huntington’s disease mouse model expressing endogenous mutant Htt. Importantly, a novel Gpr52 antagonist E7 reduces mutant HTT levels and rescues Huntington’s disease-associated phenotypes in cellular and mouse models. Our study provides an entry point for Huntington’s disease drug discovery by targeting Gpr52. |
format | Online Article Text |
id | pubmed-5972579 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-59725792018-06-04 Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes Song, Haikun Li, Hexuan Guo, Shimeng Pan, Yuyin Fu, Yuhua Zhou, Zijian Li, Zhaoyang Wen, Xue Sun, Xiaoli He, Bingqing Gu, Haifeng Zhao, Quan Wang, Cen An, Ping Luo, Shouqing Hu, Youhong Xie, Xin Lu, Boxun Brain Original Articles See Huang and Gitler (doi:10.1093/brain/awy112) for a scientific commentary on this article. Lowering the levels of disease-causing proteins is an attractive treatment strategy for neurodegenerative disorders, among which Huntington’s disease is an appealing disease for testing this strategy because of its monogenetic nature. Huntington’s disease is mainly caused by cytotoxicity of the mutant HTT protein with an expanded polyglutamine repeat tract. Lowering the soluble mutant HTT may reduce its downstream toxicity and provide potential treatment for Huntington’s disease. This is hard to achieve by small-molecule compound drugs because of a lack of effective targets. Here we demonstrate Gpr52, an orphan G protein-coupled receptor, as a potential Huntington’s disease drug target. Knocking-out Gpr52 significantly reduces mutant HTT levels in the striatum and rescues Huntington’s disease-associated behavioural phenotypes in a knock-in Huntington’s disease mouse model expressing endogenous mutant Htt. Importantly, a novel Gpr52 antagonist E7 reduces mutant HTT levels and rescues Huntington’s disease-associated phenotypes in cellular and mouse models. Our study provides an entry point for Huntington’s disease drug discovery by targeting Gpr52. Oxford University Press 2018-06 2018-03-28 /pmc/articles/PMC5972579/ /pubmed/29608652 http://dx.doi.org/10.1093/brain/awy081 Text en © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Articles Song, Haikun Li, Hexuan Guo, Shimeng Pan, Yuyin Fu, Yuhua Zhou, Zijian Li, Zhaoyang Wen, Xue Sun, Xiaoli He, Bingqing Gu, Haifeng Zhao, Quan Wang, Cen An, Ping Luo, Shouqing Hu, Youhong Xie, Xin Lu, Boxun Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes |
title | Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes |
title_full | Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes |
title_fullStr | Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes |
title_full_unstemmed | Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes |
title_short | Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes |
title_sort | targeting gpr52 lowers mutant htt levels and rescues huntington’s disease-associated phenotypes |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972579/ https://www.ncbi.nlm.nih.gov/pubmed/29608652 http://dx.doi.org/10.1093/brain/awy081 |
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