Study Reveals Possible Drug Target For Huntington’s Disease

Researchers from the Scripps Research Institute identified the protein Rhes as a crucial player in neuronal death in the striatum, the brain region responsible for motor and cognitive functions. The study entitled “Ectopic expression of the striatal-enriched GTPase Rhes elicits cerebellar degeneration and an ataxia phenotype in Huntington’s disease” was published last June in the journal Neurobiology of Disease.

Huntington’s disease is a genetic disorder caused by an expansion of glutamine repeats in the huntingtin protein (mHtt), causing the progressive degeneration of nerve cells in the striatum. The protein mHtt is expressed in several brain regions, like the cerebellum, but there is no neuronal loss in such areas. The reasons behind such phenomenons is currently not clear. Huntington’s disease has a wide impact on the functional abilities of patients leading to motor, cognitive and neurological disorders. There are drugs which can manage the symptoms of the disease but cannot prevent the physical, mental and behavioural deterioration associated with the condition.

Principal investigator Srinivasa Subramaniam explained in a news release that this work has finally confirmed the role of Rhes in Huntington’s disease. He added the next step will be to develop drugs that inhibit its activity.

In previous studies, the research team showed that Rhes binds to several repeats in the huntingtin protein increasing neuronal death. The present study revealed that deleting Rhes considerably reduced behavioural complications in animal models of the disease. Furthermore, injecting Rhes in experimental models of Huntington disease also increased motor problems, including loss of balance and coordination, while increasing the expression of Rhes in the cerebellum, a brain region normally not affected in this disease, can promote toxicity and induce lesions and damaged neurons.

“Many Huntington’s disease patients experience psychiatric-related problems, such as depression and anxiety,” added Supriya Swarnkar, the study’s first author. He added that it is not clear if these disorders are the cause or the consequence of the disease.

The authors believe Rhes is a potential drug target for Huntington’s disease since drugs that disrupt Rhes could improve Huntington’s pathology and motor symptoms and may give protection against neurological-related disorders.