Study stirs debate on cause of Huntington's disease

NEW YORK -- A surprising and provocative study of brain tissue from people with Huntington's disease will stir debate about how a defective gene causes the disorder -- and how to devise a treatment.

About 30,000 Americans have HD, which generally appears between ages 30 and 45 and slowly hampers a person's ability to walk, think, talk and reason. Eventually, an affected person becomes totally dependent on others, and death usually follows from complications of the condition.

Each child of a person with HD runs a 50 percent chance of inheriting the defective gene.

Scientists want to find out just how that gene causes the disease, so they could get clues about how to block or ease symptoms. They know the gene makes brain cells produce a defective version of a normal protein. But what happens then?

One major theory says this defective protein gets chopped into fragments, and one of those fragments is toxic to brain cells. But the new study, published online Oct. 15 by the journal Nature Genetics, challenges that idea.

Scientists report they were surprised to find that when they studied autopsy tissue from the brains of five HD patients, they found the mutant protein had actually resisted getting chopped up much more than its normal counterpart had.

What's more, they found that the mutant protein had grabbed onto its normal counterpart protein, which would have kept the normal protein from doing its job. (Nobody knows what the normal protein is supposed to do, but experiments show it is vital). And when researchers put copies of the full-length mutant protein into skin cells in a lab, the copies clumped up and killed the cells.

All in all, the new study suggests the real culprit is this sticky, full-length protein rather than any toxic fragment of it, said Cynthia McMurray of the Mayo Clinic in Rochester, Minn., senior author of the study.

It apparently kills brain cells by binding to its normal counterpart and other key players in the cell and drawing them into clumps, which keeps them from doing their jobs, she said. The full-length protein may grab onto targets the small fragments would miss, she said.