Huntington’s disease (HD) is neurodegenerative disorder. It is caused by the mutation of the HTT gene encoding the mutant HTT protein (mHTT) with expanded polyglutamine tract (polyQ).

For neurodegenerative disorders, lowering the levels of disease-causing proteins is an attractive treatment strategy. Therefore, lowering the mHTT level ameliorates mHTT toxicity in multiple models.

In a paper published in Brain, Prof. LU Boxun’s lab at Fudan University and Prof. XIE Xin’s lab at the Shanghai Institute of Materia Medica (SIMM) of Chinese Academy of Sciences revealed that targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes.

GPR52, a striatal-enriched G protein-coupled receptor, was discovered by Prof. LU Boxun’s lab to regulate the mHTT levels ex vivo and in vivo. Knocking-down GPR52 rescues HD-associated phenotypes in HD fly and mouse models and patient induced pluripotent stem cell (iPSC)-derived neurons. This indicated that GPR52 might be a potential drug target for the treatment of HD.

Prof. XIE Xin’s lab carried out a high-throughput screen and identified a specific antagonist of GPR52, compound E7. This compound reduces mHTT levels and rescues HD-associated behavioural phenotypes in a knock-in HD mouse model expressing endogenous mHTT. The data provided the proof-of-concept evidence of treating Huntington’s disease by reducing soluble mHtt via GPR52 blockade with compound drugs.

Beside Prof. XIE Xin’s lab, Prof. HU Youhong’s lab at SIMM has been focusing on optimizing the compound E7 so as to improve the antagonist activity on GPR52.

The study was supported by the Ministry of Science and Technology of China, the National Natural Science Foundation of China and Fudan-SIMM Joint Innovation Fund.