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The GPR52 Pathway and HD


 Researchers in China recently conducted a study that provided new insights into signaling pathways in the brain, and how these pathways can affect the concentration of huntingtin protein in the brain12. Huntingtin protein is an important biological agent for many facets of our bodies, including cell signaling and the transport of materials; however, literature supports that the mutation of this protein also causes the majority of symptoms in Huntington’s Disease (HD). Current treatments for HD are only able to slow, not prevent, the aggregation of mutated huntingtin proteins (mHTT). A cure for HD may require these proteins to be completely destroyed or degraded. 

This new study proposes a method wherein the levels of huntingtin protein can be decreased. The researchers targeted a specific signaling pathway in the brain called GPR52, which is a type of G-protein receptor (more on this in the next section). By blocking this path, the researchers observed significant decreases in mutant proteins. The findings and their implications are described in detail below.


What is a G-protein receptor pathway?

As noted, the researchers targeted a specific G-protein pathway called GPR52. At a basic level, these pathways are the major avenues by which our cells talk to each other. A great number of these paths exist in our bodies, and all have many different functions. However, they all function in similar manners. First, a specific molecule attaches to a receptor on the outside of the cell. Then, the receptor is activated, and sends a signal into the cell. This signal then has a specific effect, ranging from bodily functions to chemical reactions. 

The GPR52 pathway works just like the system described above. It is activated by a certain molecule, and this molecule is able to send a signal into the cell through a receptor and trigger a response. The response, in this case, relates to the huntingtin protein. When this pathway is activated, the cell responds by moving huntingtin protein to a specific compartment of the cell. In this new compartment, the huntingtin proteins can escape the typical cell machinery that would degrade them. This is inconsequential for the healthy huntingtin proteins; they are able to be processed further and do not pose any harm to the individual in this new compartment. MHTTs, however, aggregate here with no outlet for removal. Therefore, in an HD individual, these mutant proteins are allowed to avoid processes that normally would break them down, and accumulate. These protein aggregates then cause the onset of HD symptoms


Study Design

These researchers recognized that the GPR52 pathway may contribute to HD symptoms, and explored ways to utilize this pathway to treat HD. Since the activation of this pathway causes negative effects, they decided to block it using an antagonist, a type of molecule that sits in the pathway’s receptor, but has no effect. Essentially, it blocks other molecules from activating the pathway and causing the unwanted effects. They named the antagonist used in this study Comp-43. 

The study was performed on mice with the HD mutation. The researchers administered Comp-43–their blocking agent–to one group of mice, while the other mice did not receive the treatment. They then measured several aspects of the mice to determine whether the compound had a significant effect on HD. These aspects include mHTT levels, total neuron levels, and brain inflammation, all of which studies have shown to be indicators of HD severity. 



The researchers produced several noteworthy findings. The first factor they measured was mHTT levels, which is a major cause of HD symptoms. The group that received the experimental agent Comp-43 saw over a 20% reduction in their mHTT levels. This reduction, the researchers noted, was enough to restore normal function to HD mice. However, Comp-43 also targeted the healthy form of huntingtin protein, which is necessary for normal bodily functions. The researchers maintained that this reduction was within a safe level; in fact, previous studies have shown that a 50% reduction in total huntingtin protein levels is manageable. 

They also measured total neuron concentrations in the striatum, the area of the brain most affected by HD. The mutant huntingtin protein mHTT typically targets this area, destroying neurons or decreasing their functioning. Besides decreasing mHTT levels, many novel therapies target the striatum to help restore functioning in HD individuals. For this study, the researchers found that the administration of the experimental Comp-43, neuronal loss and neuron death was prevented. This allowed the mice to regain motor function and greatly improved their HD symptoms, indicating a strong effect. 



These preliminary findings demonstrate great promise for GPR52 treatments and compounds like Comp-43. The most encouraging part of their research is that blockage of this pathway seems to reduce mHTT levels. Many therapies are incapable of doing so, only slowing the progression of mHTT accumulation. Similarly, many treatments are minimally effective or fail completely to protect against neuron loss. Both of these aspects set this treatment apart, and show great efficacy. 

There are a few considerations, however, when discussing this research. For one, it is important to remember that this was a mouse model. Expanding this treatment into humans will take time and much more research, and Comp-43 is not yet a viable drug for HD individuals. Its effects must also be studied more closely. As noted above, the GPR52 pathway is integral in much more than just regulating the huntingtin protein. It also has major effects on the neurotransmitter dopamine, which can control both movement and mood. While the researchers did not observe any erratic behavior in their study, more research is necessary to ensure any future drugs targeting GPR52 do not have unwanted effects on brain chemistry.

  1. Wang, C.; Zhang, Y.-F.; Guo, S.; Zhao, Q.; Zeng, Y.; Xie, Z.; Xie, X.; Lu, B.; Hu, Y. GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington’s Disease-Related Phenotypes. J. Med. Chem. 2020 []
  2. Komatsu, Hidetoshi. Discovery of the First Druggable GPR52 Antagonist to Treat Huntington’s Disease. J. Med. Chem. 2021 []