A new study casts doubts on a long-held theory about what goes awry in the brains of patients with Huntington's disease. The results suggest new approaches to designing drugs against the fatal neurological disorder.
Huntington's patients have a mutant form of a protein called huntingtin that contains between 36 and 120 repeats of the amino acid glutamine, where unaffected individuals have just a couple dozen repeats. Scientists have long assumed that the disorder arose from the interaction between huntingtin and so-called caspases, enzymes involved in the routine breakdown of proteins. When caspases chopped off small peptides from the mutant region of huntingtin, they thought, the peptides accumulated into the abnormal globs seen in the neurons of Huntington's victims. In lab experiments, the same peptides kill nerve cells.
But in the 15 October online issue of Nature Genetics, geneticists Roy Dyer and Cynthia McMurray at the Mayo Clinic in Rochester, Minnesota, report that the theory does not stand up to rigorous examination. When they stained brain samples taken from human Huntington's victims, they found that the characteristic globs consist of full-length mutant huntingtin, rather than peptide fragments from the mutant. Next, they showed that caspases don't chop off peptides of the mutant protein at all. Instead, the caspases break down normal huntingtin protein, as they're supposed to. Things go awry when these fragments are drawn toward the globs of abnormal huntingtin, instead of being processed further. The researchers speculate that this interaction eventually kills the cell, although they're not sure how.
The study is "very important" and shows that the prevailing explanation for the origin of Huntington's disease needs to be "reshuffled," says Scott Zeitlin, a neuroscientist at the University of Virginia in Charlottesville. Zeitlin says the study may also help researchers find new targets for drugs against Huntington's--such as compounds that block the clumping of abnormal huntingtin.