Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes

  • Brain. 2018 Jun 1;141(6):1782-1798. doi: 10.1093/brain/awy081.
Haikun Song  1 ,  Hexuan Li  1 ,  Shimeng Guo  2 ,  Yuyin Pan  1 ,  Yuhua Fu  1 ,  Zijian Zhou  1 ,  Zhaoyang Li  1 ,  Xue Wen  1 ,  Xiaoli Sun  1 ,  Bingqing He  2  3 ,  Haifeng Gu  2 ,  Quan Zhao  1 ,  Cen Wang  1 ,  Ping An  1 ,  Shouqing Luo  4 ,  Youhong Hu  2 ,  Xin Xie  2  3 ,  Boxun Lu  1
Affiliations
  • 1. Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology, School of Life Sciences, Fudan University, Shanghai, China.
  • 2. CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 4. Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Research Way, Plymouth, UK.
PMID: 29608652 DOI: 10.1093/brain/awy081
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.

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