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New model of Huntington's disease
Edward R. Winstead

A new study of Huntington's disease finds that the main offender in the brain is a mutant protein, called 'huntingtin,' in its full-length form. This mutant HD protein damages the brain by isolating other molecules that are needed to carry out essential functions in the cell.

Normal HD protein is chopped up by enzymes in the brain. Cynthia T. McMurray and Roy B. Dyer, of the Mayo Clinic and Foundation in Rochester, Minnesota, discovered that mutant protein is more resistant to enzymes than is normal HD protein. They also found that mutant protein causes disease by targeting other molecules, including fragments of the normal HD protein.

"Our data from multiple human brains confirm that normal HD is indeed targeted by the mutant protein in Huntington disease-affected brain," the researchers write in an advance online publication of Nature Genetics. "The mutation may result in the loss of normal HD function."

Previous studies suggest that Huntington's is primarily due to the accumulation of toxic fragments from mutant HD protein. McMurray and Dyer were analyzing tissue from autopsied patients and rats with the disease when they discovered, unexpectedly, that more than 90 percent of mutant protein survives in its full-length form.

The underlying genetic flaw in the disease is a stretch of DNA within the huntingtin gene that grows larger over time and results in the mutant protein. This leads to a progressive loss of motor control and cognitive ability, and there is no cure.

One goal of therapies under development is to block enzymes that cut mutant protein. The new findings suggest that mutant fragments may be less harmful than full-length protein because they accumulate fewer molecules.

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Dyer, R.B. & McMurray, C.T. Mutant protein in Huntington disease is resistant to proteolysis in affected brain. Nat Genet. Published online October 15, 2001.

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