Tantalizing Clues Emerging in Bid to Understand Huntington’s Disease

A surprising and provocative study of brain tissue from people with Huntington’s disease offers clues on how a defective gene causes the disorder and how it might be treated.

About 30,000 Americans have HD, which generally appears between ages 30 and 45. It 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% chance of inheriting the defective gene.

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

One 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.

“This shifts the thinking on what is going on in Huntington’s disease,” McMurray said. “We think it sets a new tone for the field and sheds light on the disease pathway and therapy.”

For one thing, she said, it suggests that trying to find ways to prevent the chopping up of the mutant protein won’t be the most effective strategy to help treat the disease. Instead, she and other scientists are trying to develop substances to stop the mutant protein from being so sticky-fingered. That work is in its early stages, she said.

Dr. Christopher Ross, who studies HD at the Johns Hopkins School of Medicine in Baltimore, said earlier studies in mice had also suggested the full-length mutant protein was to blame. But McMurray’s paper provides much stronger evidence, he said.

“I’m still not sure I agree with her,” said Ross, who favors the toxic-fragment theory.

But the new work “certainly makes a provocative and strong case” and it will generate controversy in the field, Ross said.

If nothing else, he said, “it’s going to stimulate me to go back in the lab” to find more evidence for the toxic-fragment idea.

*

Information on Huntington’s disease: www.hdsa.org

Nature Genetics:

https://genetics.nature.com