Study identifies key protein linked to brain damage in Huntington's

The location of a faulty protein seems to explain the pattern of brain damage and symptoms of people with Huntington's disease, researchers say.

Huntington's disease is caused by an inherited gene mutation that codes for a protein called huntingtin, which gathers in all cells of the body but only seems to cause damage in the brain. 

'The answers in one disease may have implications for another.' — Dr. Walter Koroshetz

"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, whose team reported the findings in Friday's edition of the journal Science.

The disease causes uncontrolled twitches and jerks that are irreversible and deteriorates into loss of intellectual function and the inability to walk, talk and swallow.

Symptoms typically start in the late 30s or early 40s, and death occurs a decade or more after symptoms begin.

In people with Huntington's, the neurons that die off are mostly in the part of the brain that controls movement — the corpus striatum.

Snyder and his colleagues found that a protein called Rhes, found almost exclusively in the corpus striatum, mixes with the mutated Huntington's protein, causing a chemical reaction.

The researchers then experimented on human embryonic cells and brain cells taken from mice, adding different combinations of normal and mutant Huntington protein and Rhes protein.

The cells were examined over the next week to see if any died.

Adding each protein individually didn't make any difference, but when both proteins were present in the same cells, half the cells died within 48 hours, the researchers found.

"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 in a news release. "And it turns out it looks like the key to Huntington's disease."

Clump cause-and-effect clue

There is an ongoing debate among researchers about whether clumps — aggregates of faulty protein — found in the brain in diseases like Huntington's and Alzheimer's are toxic to the brain or whether it's a lack of clumps that prevents the brain from saving itself.

In the study, adding Rhes to cells with abnormal Huntington led to fewer clumps, but the cells still died.

The results suggest Rhes might be responsible for unclumping mutant Huntington in the brain, leading to death of neurons, said study co-author and postdoctoral researcher Srinivasa Subramaniam.

Since Rhes is not found elsewhere in the body, those tissues might stay clumped and protected, Subramaniam said.

"The answers in one disease may have implications for another," said Dr. Walter Koroshetz, deputy director of the U.S. National Institutes of Health's brain division

"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 [unclumped] protein as being the major problem."

If tests show removing Rhes from mice with Huntington's disease slows or prevents the brain cell death without causing too many side-effects, the findings could offer a new drug development target for researchers.

"This is a very promising avenue," said Dr. Nancy Wexler of the Hereditary Disease Foundation, who helped lead the research that resulted in the discovery of the Huntington's gene in 1993.