ORCID
- Luo, Shouqing: 0000-0002-7998-3059
Abstract
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.
DOI
10.1093/brain/awy081
Publication Date
2018-06-01
Publication Title
Brain
Volume
141
Issue
6
First Page
1782
Last Page
1798
ISSN
0006-8950
Embargo Period
2018-06-15
Organisational Unit
Peninsula Medical School
Recommended Citation
Song, H., Li, H., Guo, S., Pan, Y., Fu, Y., Zhou, Z., Li, Z., Wen, X., Sun, X., He, B., Gu, H., Zhao, Q., Wang, C., An, P., Luo, S., Hu, Y., Xie, X., & Lu, B. (2018) 'Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes.', Brain, 141(6), pp. 1782-1798. Available at: https://doi.org/10.1093/brain/awy081
