Huntington’s Disease Protein May Have An Accomplice

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Experiments could explain why only some neurons in the brain are vulnerable to the disease By Tina Hesman Saey, Science News

Researchers may have discovered how a neuron-killing protein selects its victims — it has an accomplice.

• Scientists identified a mutant form of the protein huntingtin as the culprit in Huntington’s disease in 1993. The protein is found in every cell in the body, but it only turns deadly in brain cells — particularly cells in the striatum, a part of the brain that helps control movement. Why mutant huntingtin preferentially kills those cells has been a mystery.
• Now, researchers at Johns Hopkins University in Baltimore report in the June 5 Science that a protein called Rhes may goad huntingtin into killing brain cells in the striatum, leading to Huntington’s disease. If confirmed, the finding could provide new avenues for developing therapies to treat the fatal neurodegenerative disease, says Nancy Wexler, president of the Hereditary Disease Foundation and a Huntington’s disease researcher at Columbia University.
• “This study really gave me a peek into what the future of the field might look like,” says William Seeley, a neurologist at the University of California, San Francisco’s Memory and Aging Center. Many researchers study the role of individual proteins in causing or preventing disease, but few studies before this one go beyond the molecular level and explain why neurodegenerative diseases attack only certain parts of the brain. “What makes it so special for me is that it builds a bridge back to the anatomy of the disease,” Seeley says.
• Solomon Snyder, a neuroscientist at Johns Hopkins University, and his team investigated the protein Rhes (a nickname for Ras homolog enriched in striatum), which is produced mostly in the striatum. The researchers found that Rhes interacts with huntingtin, and the association is even stronger with the disease-causing form of huntingtin. The scientists grew human embryonic cells and mouse brain cells in petri dishes, and produced the two proteins (Rhes and the mutant form of huntingtin) in the cells. Cells making either protein alone stayed healthy, but cells that contained both proteins quickly died.
• Through a process called sumoylation, Rhes adds another, small protein called SUMO to huntingtin, the team discovered. Usually, the mutant form of huntingtin just forms big clumps in cells, but adding SUMO seemed to partially dissolve the clumps, leading to cell death. The researchers suggest that the clumping renders the mutant form of huntingtin harmless, but that sumoylation makes the protein soluble and thus toxic. Why is unclear.
• Future drugs that would block the interaction of Rhes with the mutant huntingtin protein or that would stop sumoylation could prevent or delay the development of Huntington’s disease, Snyder says.
• But some Huntington’s disease researchers are not as enthusiastic about the new study. “It’s of questionable relevance,” says Jang-Ho Cha of Massachusetts General Hospital’s Institute for Neurodegenerative Disease in Charlestown. “You can model things in a dish, but does it have anything to do with the way cells die in a Huntington’s disease brain?”
• Other researchers agree that much more research is needed, particularly experiments in mice that might show whether removing Rhes could prevent the mutant huntingtin protein from becoming toxic. “There’s still a long way to go,” says Carl Johnson, executive director for science for the Hereditary Disease Foundation. But, “there’s no doubt about the correctness of the results that are presented in the paper.”