Scientists from the Florida campus of The Scripps Research Institute (TSRI) have established conclusively that an activating protein, called “Rhes,” plays a pivotal role in focusing the toxicity of Huntington’s in the striatum, a smallish section of the forebrain that controls body movement and is potentially involved in other cognitive functions such as working memory.
“Our study definitively confirms the role of Rhes in Huntington’s disease,” said TSRI Assistant Professor Srinivasa Subramaniam, who led the study. “Our next step should be to develop drugs that inhibit its action.”
The study was published recently online ahead of print by the journal Neurobiology of Disease.
In an earlier study, Subramaniam and his colleagues showed that Rhes binds to a series of repeats in the huntingtin protein (named for its association with Huntington’s disease), increasing the death of neurons. The new study shows deleting Rhes significantly reduces behavioral problems in animal models of the disease.
In addition, the study took the research further and revealed the effects of adding Rhes to the cerebellum, a brain region normally not affected in Huntington’s.
Remarkably, Huntington disease animals injected with Rhes experienced an exacerbation of motor issues, including loss of balance and coordination. Subramaniam and his colleagues also found lesions and damaged neurons in the cerebellum, confirming Rhes is sufficient to promote toxicity and showing that even those regions of the brain normally impervious to damage can become vulnerable if Rhes is overexpressed.
“Perhaps the biggest question to emerge from this study is whether Rhes is a good drug target for Huntington’s disease,” Subramaniam said. “The short answer is ‘yes.’ Drugs that disrupt Rhes could alleviate Huntington’s pathology and motor symptoms.”
“Many Huntington’s disease patients experience psychiatric-related problems, such as depression and anxiety,” added Supriya Swarnkar, the first author of the study and a member of Subramaniam’s lab. “But it’s unclear whether they are the cause or consequences of the disease. We think, by targeting Rhes, we might block the initiation of Huntington’s, which we predict would afford protection against psychiatric-related problems as well.”
In addition to Swarnkar and Subramaniam, other authors of the study, “Ectopic Expression of the Striatal-enriched GTPase Rhes Elicits Cerebellar Degeneration and an Ataxia Phenotype in Huntington Disease,” are Youjun Chen, William Pryor, Neelam Shahani and Damon Page of TSRI. See http://www.sciencedirect.com/science/article/pii/S0969996115001850
The work was supported by the State of Florida.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates—work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
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