June 22, 2009

Scientists Identify Culprit in Huntington’s Disease

Image of yellow dots in red brain cell Mutant huntingtin proteins (yellow) abnormally clump in mouse brain cells.Wellcome Images

Scientists have solved why a faulty protein accumulates in cells throughout the body in people with Huntington's disease, but only kills certain brain cells. It has an accomplice. The discovery provides a potential target to treat or slow the progression of Huntington's.

Huntington's disease is a rare neurodegenerative disorder that affects an estimated 30,000 people nationwide. Symptoms, which appear in the late 30s and 40s, include uncontrollable twitches and jerks and a deterioration of mental abilities. Death typically comes about a decade after symptoms begin.

Huntington's is a familial disease, passed from parent to child through a mutation in the huntingtin gene. The mutant huntingtin protein abnormally accumulates and clumps in all cells throughout the body. But for reasons scientists didn't understand, mutant huntingtin protein only destroys brain cells in the area of the brain responsible for movement, called the corpus striatum. The mutant protein causes little damage in other tissues.

A research team at Johns Hopkins led by Dr. Srinivasa Subramaniam and Dr. Solomon H. Snyder searched for proteins that interacted with mutant huntingtin protein solely in the corpus striatum. They reasoned that these unique proteins would provide clues to the huntingtin protein's brain-specific effect. Their work was funded by NIH's National Institute of Mental Health (NIMH) and National Institute on Drug Abuse (NIDA).

The researchers focused their attention on the protein Rhes, which is exclusively found in the corpus striatum. In the June 4, 2009 issue of Science, they reported that the Rhes protein interacts with both healthy and mutant versions of the huntingtin protein in human and mouse cells. But the Rhes protein binds much more strongly to mutant huntingtin.

Using a human cell line and mouse brain cells, the scientists added different combinations of normal and mutant huntingtin and Rhes. While each protein alone did not change the survival of the cells, Rhes and mutant huntingtin together caused 50% of the cells to die within 48 hours.

The researchers also found that, in the cells expressing both Rhes and mutant huntingtin, the mutant huntingtin protein no longer clumped. Rhes, they discovered, adds a small protein called SUMO to mutant huntingtin—a process called sumoylation. Sumoylation of mutant huntingtin partially dissolves the protein clumps into a soluble toxic protein. These results suggest that clumping somehow protects cells in other tissues of the body from dying. It's still unclear why the soluble mutant huntingtin leads to cell death.

The scientists are currently testing to see if removing Rhes from mice with Huntington's disease can slow or stop brain cells from dying. Future treatment strategies for the disease could aim to block the interaction of Rhes with mutant huntingtin or stop sumoylation.

"Now that we've uncovered the role of Rhes, it's possible that drugs can be designed that specifically target Rhes to treat or even prevent the disease," Snyder says.

These findings may have implications far beyond Huntington's disease. Understanding the underlying mechanism behind this disease could lead to insights into other neuropsychiatric diseases and conditions that involve localized damage.

—by Nancy Van Prooyen

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