Discovery Sheds Light on Huntington's Disease

THURSDAY June 4, 2009 -- Scientists have pinpointed a protein that plays a key role in cell death in Huntingdon's disease, a degenerative disorder that leads to uncontrolled movements and loss of intellectual functioning.

The discovery raises hope that drugs could be developed to slow or halt the disease, according to a study in the June 5 issue of Science.

In Huntington's disease, cells in the corpus striatum, the area of the brain that controls movement, gradually die off.

Previous research has shown that people with Huntington's have a genetic defect that produces a mutant version of the protein "huntingtin," which accumulates in cells throughout the body.

But for reasons scientists didn't understand, the protein only kills cells in the corpus striatum. The protein causes little damage to tissues elsewhere.

In the new study, researchers discovered that a tiny protein called "rhes" -- found only in the corpus striatum -- interacts with the mutant huntingtin proteins, causing cell death.

The findings explain the pattern of brain damage in Huntington's disease and suggest strategies for developing new drug therapies, researchers at Johns Hopkins University said.

"It's always been a mystery why, if the protein made by the HD (Huntington's disease) gene is seen in all cells of the body, only the brain, and only a particular part of the brain, the corpus striatum, deteriorates," said Dr. Solomon H. Snyder, a professor of neuroscience at Johns Hopkins. "By finding the basic culprit, the potential is there to develop drugs that target it and either prevent symptoms or slow them down."

Huntington's is a familial disease, passed from parent to child through a gene mutation. A child of someone with Huntington's has a 50-50 chance of inheriting the gene, according to the National Institute of Neurological Disorders and Stroke.

Because the damage from the faulty gene is limited to the corpus striatum, researchers went searching for proteins that interacted specifically and exclusively with the huntingtin protein in that part of the brain.

Rhes is found almost exclusively in the corpus striatum, according to the study.

Using human and mouse cells, researchers found that rhes interacted with both healthy and mutant versions of huntingtin protein, but that it bound much more strongly to mutant huntingtin, also known as mHtt.

"Touching or binding is one matter, but death is altogether another," Snyder said.

Further tests using human embryonic cells and brain cells taken from mice showed that when both mHtt and rhes were present in the same cells, half the cells died within 48 hours. Rhes or mHtt alone did not cause cell death.

"Here's the rhes protein, we've known about it for years, nobody ever really knew what it did in the brain or anywhere else," Snyder said. "And it turns out it looks like the key to Huntington's disease."

Researchers also did a set of tests to learn more about the role of rhes. Previous research has shown that the abnormal huntingtin proteins form clumps in cells throughout the body and brain, but that there are fewer of the clumps in the corpus striatum.

"This has led to much controversy: Are the clumps toxic, or is it the lack of clumps that's toxic to these brain cells?" said Srinivasa Subramaniam, a postdoctoral fellow at Johns Hopkins.

Experiments showed that adding rhes to cells with abnormal huntingtin led to fewer clumps, but the cells died.

Researchers said that the unclumping of mutant huntingtin proteins by rhes might cause the cell death.

"Since rhes is highly found in the corpus striatum, clumping somehow protects cells in other tissues of the body from dying," Subramaniam said.

The team is currently testing to see if removing rhes from mice with Huntington's disease can slow or stop brain cells from dying.

"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 said.

More information

The National Institute of Neurological Disorders and Stroke.

Posted: June 2009


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