Rewriting the Book on Huntington's Disease

Buildup of mutant protein turns off normal protein, says study

MONDAY, Oct. 15, 2001 (HealthDayNews) -- "Sticky" mutant proteins latch onto normal Huntington's proteins, kidnapping and deactivating them so that the bloated mutant accumulates and over time causes the full-blown genetic disease, a new study suggests.

If confirmed, the finding means Huntington's researchers may have to make a course correction in their search for how the degenerative and ultimately fatal, genetic brain disorder progressively destroys the ability to think, walk and talk.

The current idea is that a fragment of the mutant protein needs to be broken off for the full-blown disease to develop, say researchers at the Mayo Clinic in Rochester, Minn. Their findings appear in the November issue of Nature Genetics.

Roughly 30,000 Americans have HD, while another 150,000 are at risk of developing the disease. The child of a parent with HD has a 50-50 chance of inheriting the gene responsible for HD, and everyone who inherits the gene will develop the disease.

Early symptoms of HD, including problems thinking or moving, mood swings, clumsiness and involuntary twitching, typically appear between ages 30 and 45. Eventually, a person with HD can't walk, speak or swallow, and death results from complications such as choking, infection or heart failure.

The HD gene was isolated in 1993, leading to a test that can accurately determine whether a person carries the HD gene, but the disease has no cure or treatment.

"The first event after the gene [was] cloned was that many groups tried to make a mouse model using the full gene," says senior author Cynthia McMurray, a professor of molecular pharmacology and experimental therapeutics at the Mayo Clinic. "When several groups tried to make these models … it looked like somehow, with the full-length gene, we couldn't reproduce the disease in an animal."

Later studies showed that the animals did develop some neurological problems later in life, but surprisingly, not full-blown HD. McMurray says this was a problem for researchers who need animal models to understand the disease and create therapies.

Huntington's researchers began to suspect that a so-called "N-terminal fragment" had to be clipped off the mutant HD protein for the disease to develop. Later studies showed that the clipped N-terminal fragment was, in fact, toxic to cells, and since then research has focused on this model.

But McMurray was bothered by the fact that no solid evidence showed that the N-terminal fragment was released in the disease. At the same time, the extreme and rapid toxicity of the fragments suggested their effect should occur quickly; yet HD takes a long time to appear.

McMurray and colleague Roy Dyer examined tissue from the autopsied brains of Huntington's patients, genetically engineered animals and diseased cells, and compared them to normal tissues and cells. They were surprised by what they found.

Rather than a clipped mutant protein, McMurray discovered the protein resists being broken down and remains full length. "Because it wasn't broken down, it starts accumulating in the neurons," says McMurray.

Moreover, they found that the N-terminal fragments came from the breakdown of normal HD protein. McMurray says the accumulated full-length mutant proteins are "sticky" and grab hold of normal Huntington's protein and the normal N-terminal fragments.

McMurray suggests that the toxic effects that lead to HD symptoms develop because the normal protein, which is crucial to healthy cell function, becomes inaccessible.

"We cannot live without a Huntington protein," says McMurray. "If the mutant [protein] grabs the normal [protein] and doesn't allow it to work, it means the cell is depleted of any Huntington protein."

"In essence, even though you're expressing the [normal] protein, the mutant takes it out and prevents it from functioning," says McMurray.

The accumulation of the mutant protein takes time, which would explain the delayed onset of HD, she says.

The possibility that the mutant protein is not clipped challenges another assumption about Huntington's, says McMurray. Until now, researchers had thought that the smaller N-terminal fragments were able to penetrate the cell nucleus, one of the areas in which buildup occurs.

But since the mutant protein appears to remain whole, McMurray says that suggests that early in the course of the disease, the entire cell changes, allowing the mutant protein into the nucleus.

"If we're thinking of therapy, we're going to have to look at this early event because by the time it gets to the nucleus, it's too late," says McMurray.

McMurray says the findings, if confirmed by other laboratories, will change how researchers make animal models for HD. At the same time, she says research that until now has looked for ways to prevent the clipping of the mutant protein now will turn to preventing the accumulation of the full-length mutant protein.

She says the finding will "fundamentally shift the field." However, she says the approach is not so different that it will set Huntington's research back.

Scott Zeitlin, assistant professor of neuroscience at the University of Virginia School of Medicine in Charlottesville, says new approaches to therapy could either attempt to protect the normal protein or help the cell deal with the mutant protein.

He says patients and their families need to be patient because the research is basic and won't lead to immediate treatments for HD.

"In all of this basic research, it gives you new opportunities to think about the problem and to design alternate therapeutic approaches," says Zeitlin. "The more different approaches that are available, the better the chance of finding something that, in the end, will be very effective."

What To Do: To find out about HD, check the Huntington's Disease Society of America, the National Institute of Neurological Disorders and Stroke or the International Huntington Association.

SOURCES: Interviews with Cynthia T. McMurray, Ph.D., professor, department of molecular pharmacology and experimental therapeutics, Mayo Clinic and Foundation, Rochester, Minn., and Scott O. Zeitlin, Ph.D., assistant professor, department of neuroscience, University of Virginia School of Medicine, Charlottesville, Va.; November 2001 Nature Genetics
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