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Accomplice Protein Gives Hope To Huntington’s Research

June 5, 2009

Researchers say they have made a significant breakthrough in understanding the mechanism by which Huntington’s disease selectively destroys only certain brain cells in patients afflicted with the illness.

Experts say the discovery could provide them with a target against which to develop and direct long-awaited treatments for the fatal disease.  They also hinted that their new understanding could prove significant for research on more common degenerative brain disorders such as Alzheimer’s.

“Up until now, nobody had the vaguest notion of what was the cause of the brain damage and the death,” said Dr. Solomon Snyder of Johns Hopkins University, head of the research team whose findings were published in Friday’s edition of the journal Science.

“This is a significant step forward,” added Dr. Walter Koroshetz, deputy director of the National Institutes of Health’s brain division.

Huntington’s is a relatively rare inherited genetic disease, affecting an estimated 30,000 patients in the United States. Onset of the disorder typically occurs in the late 30s or early 40s and begins with uncontrollable muscle twitching.  As the disease progresses, the mental faculties slowly deteriorate until patients are no longer able to eat, speak or walk. Death usually occurs approximately ten to twelve years after the initial symptoms are first observed.

In 1993, scientists were able to show that a single mutated gene is responsible for the horrific disorder. Because the defective gene for the disease is dominant, children of Huntington’s patients have a 50 percent chance of inheriting that gene, and thus contracting the disorder.

Some 16 years after the gene was first discovered, there is still only one treatment available for those afflicted by the disease, and it is only effective in suppressing the uncontrollable twitching movements associated with the later stages of the disorder and has no affect in retarding the progress of the disease itself.

The defective gene responsible for Huntington’s codes for a faulty protein produced in all the body’s cells. Yet what has perplexed scientists since the gene’s discovery is the fact that only a select group of cells “” those in the movement-controlling area of the brain known as the corpus striatum “” are affected by the defective proteins.

The breakthrough made by research team at Johns Hopkins was the discovery of a second accomplice protein known as Rhes, located almost exclusively in the corpus striatum. Researchers say that when the relatively small biomolecule combines with the mutated Huntington’s protein it appears to initiate a dangerous chemical reaction.

Snyder’s team examined the effects of different combinations of the mutated Huntington’s protein on human embryonic cells and brain cells taken from mice. They found that both types of cells began dying only when the defective mutated protein and Rhes were both present in the mixture.

The researchers then turned their efforts to understanding the nature of the lethal chemical interplay of these two proteins.  They found that while the Huntington’s protein alone is insoluble and tends to be dealt with by cells as common cellular waste, the Rhes molecule binds to the protein and increases its solubility, suggesting that it is likely the soluble version that is able to wreak havoc on brain cells.

A number of other neurodegenerative disorders such as Alzheimer’s are also characterized by clumps of insoluble, deformed proteins, and there has been much debate in the research community as to whether these insoluble proteins””known as “aggregates”"”are themselves causes or merely signs of the disease.

“The answers in one disease may have implications for another,” said Dr. Koroshetz. “There’s been people on both sides of the fence. This story plays to the role of the aggregates as not being the major problem but the soluble protein as being the major problem.”

Dr. Nancy Wexler, lead researcher for the team that discovered the Huntington’s gene in 1993, hailed the new research as a “fabulous experiment” and praised the Hopkins team for quickly publishing their research so that other scientists could start work immediately on finding ways to block the lethal protein combination.

“This is a very promising avenue,” she said.

The researchers explained that one potential next step will be to determine whether the removal of the Rhes molecule from mice with Huntington’s disease is able to retard or stop the death of brain cells without also instigating damaging side effects. If this proves successful, scientists are sure to begin the race to produce a drug capable of blocking the activity or even production of the Rhes protein.

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