Drug Discovery Opinion

DDO Limited – Consultancy for Biotech and Pharma

Jun 15 2009

Rhes Protein Linked to Cell Death in Huntington’s Disease

Posted by SR in News, tags: Huntington's, neurology, target identification

Huntington’s disease (HD) is an inherited neurological disorder that causes a wide range of symptoms including involuntary movements, clumsiness, lack of concentration, memory lapses, mood swings, and depression. Although the disease mechanism is not fully understood, it is known that sufferers have a defect on the short arm of chromosome 4 and produce abnormal versions of the protein, huntingtin. One of the puzzles surrounding the progression of HD has been that, although abnormal huntingtin proteins accumulate in cells everywhere in the body, they predominantly kills cells in the corpus striatum, the part of the brain that controls movement.

Writing in the journal Science, scientists at John Hopkins School of Medicine now report that the answer may lie with the small G protein, Rhes (Ras homologue enriched in striatum), which is found almost exclusively in the corpus striatum. In cell culture experiments using both mouse and human cells, Rhes was found to bind much more tightly to mutant huntingtin than to normal protein. When added singly to cell cultures, neither Rhes nor mutant huntingtin had any effect on survival but, when they were added together, half of the cells died within 48 hours.

Abnormal huntingtin proteins aggregate and form clumps, but there are fewer of these clumps in the corpus striatum of HD patients than in other brain regions or elsewhere in the body, suggesting that clumping of the protein may actually protect the cells. The team found that, in their cell culture experiments, adding Rhes to cells with abnormal huntingtin led to fewer clumps, although the cells died. The results suggest clumping of abnormal huntingtin may prevent it from causing cell death and that Rhes might be responsible for preventing abnormal protein from clumping. Rhes was also shown to promote sumoylation of mutant huntingtin. The team are currently exploring whether removing Rhes from mice with HD will prevent cell death, and hope that it may eventually be possible to design drugs which will specifically target Rhes to treat HD.

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