Blocking Gpr52 Receptor Improves Huntington’s Symptoms in Animal Models, Study Finds

Targeting the Gpr52 receptor can reduce the levels of mutant huntingtin (HTT) proteins and improve Huntington’s disease symptoms, including walking problems, in animal models, a study suggests.

The study, “Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes,” was published in the journal Brain.

G protein-coupled receptors (GPCRs) are most frequently the targets of therapies approved by the U.S. Food and Drug Administration. A member of the GPCR family, the Gpr52 receptor is located in the cellular membrane and is involved in signal transduction from the outside to the inside of the cell.

Researchers had previously shown that the Gpr52 receptor regulates levels of mutant HTT proteins. In fact, reducing or completely eliminating the function of Gpr52 was able to improve symptoms associated with Huntington’s disease in fruit fly models and patient’s nerve cells.

Building on this knowledge, researchers tested Gpr52’s role in a mouse model of Huntington’s disease, hypothesizing that it could be a potential therapeutic target for the disease.

Results showed that a lack of Gpr52 significantly improved certain symptoms in the Huntington’s mouse model, such as walking problems, which included more frequent stops, trembles, head turns, and irregular steps.

By assessing mice walking patterns, using a tool that captures videos of walking behavior and the gait of mice passing through a lane, researchers observed that animals who lacked Gpr52 had less problems with walking.

Similar improvements were observed in an open-field test, a general motor activity test that also assesses anxiety and the animals’ natural willingness to explore. Lack of Gpr52 significantly improved Huntington’s disease-associated symptoms in the open-field test in terms of distance traveled, movement across and through the field, and the ratio of time spent in the center of the field versus time spent next to walls.

Absence of Gpr52 reduced the levels of both soluble and aggregated mutated HTT proteins in the brain of the Huntington’s mouse model.

Because Gpr52 regulates the levels of mutated HTT proteins, the team screened small molecule compounds from the Chinese National Compound Library to identify potential candidates to block Gpr52’s activity.

Out of 40,000 molecules tested, one — called AD31E7 (E7) — showed a significant inhibitory effect on Gpr52 both in cell lines and in the Huntington’s disease mouse model, and was able to reduce the levels of mutated HTT proteins and improve Huntington’s disease-associated symptoms in the mice.

“Our study provides an entry point for Huntington’s disease drug discovery by targeting Gpr52,” the researchers wrote. “Once a high-efficacy compound has been identified by optimizing the structure of E7 or additional screening, the compound will be tested for its penetration of the blood–brain barrier, its pharmacokinetics/pharmacodynamics properties and its safety profiles for further drug discovery purposes.”