Scientists at the Buck¹ Institute for Age Research have discovered that a particular family of enzymes²（酶） are involved in the breakdown³（分解，故障） of proteins that modify the production of toxic⁴ fragments that lead to the pathology（病理学） of Huntington's disease. These enzymes, matrix metalloproteinases（金属蛋白酶） (MMPs), provide new targets for drug therapies for the disease – targets that have already been shown to respond to cancer drugs currently in clinical development. Results of the research, from the laboratories of Buck faculty⁵ members Lisa Ellerby, Ph.D. and Robert Hughes, Ph.D., appear as the cover story in the July 29, 2010 edition of Neuron. Huntington's disease (HD) is an incurable⁶ progressive neurodegenerative（神经变性的） genetic⁸ disorder⁹ which affects motor coordination¹⁰ and leads to cognitive¹¹ decline and dementia（痴呆） . Symptoms usually begin to occur in middle age; patients are often totally incapacitated（丧失能力） prior to death. The worldwide prevalence of HD is 5-10 cases per 100,000 people; the rate of occurrence is highest in peoples of Western European descent.

The disease stems from a mutation¹² in the huntingtin gene⁷, located on human chromosome¹³ four. The mutation causes abnormalities in the huntingtin protein (mutantHtt, or mHtt). The pathology of HD is accelerated when mHtt is cut into smaller, highly toxic fragments via various molecular¹⁴ activities. Dr. Ellerby said to date, scientific queries¹⁵ into how those fragments are cut have focused primarily on caspases（凋亡蛋白酶） , a family of intracellular（细胞内的） proteins that mediate¹⁶ cell death, and calpains（钙激活酶） , enzymes regulated by the concentration of calcium¹⁷ ions. The Buck Institute study involved proteases, various enzymes that catalyze¹⁸ the breakdown of proteins in reaction to water. Dr. Ellerby said this research marks the first time all of the 514 different types of proteases found in humans were individually screened in cell culture to see how they affect mHtt proteolysis（蛋白质水解） . Buck Institute researchers identified 11 proteases that, when inhibited¹⁹, reduced the accumulation of toxic fragments associated with HD.

Four of the proteases belong to a family called matrix metalloproteinases (MMP), a class of enzymes already involved in drug development, Dr. Ellerby said. "We've found a target that has known drugs for cancer treatment that could possibly have significance for HD," added Dr. Ellerby. "MMPs are also involved in stroke, inflammation and many neurological processes; we expect a lot of scientific attention to now be focused on this important class of proteases," she said.

Results involving MMPs were verified in mouse models of HD, Dr. Ellerby said. In collaborative（合作的，协作的） studies with Dr. Juan Botas at Baylor College of Medicine in Houston, researchers found that homologs（同系物） of MMPs suppressed HD-induced neuronal dysfunction（功能紊乱，机能障碍） in fruit flies. "The next step in this research will be to test some of the MMP inhibitor（抑制剂） drugs as a potential treatment in HD mouse models," said Dr. Ellerby. "We'll also be crossing mice that no longer have particular MMPs with those who have HD to see what effect that has on offspring," she said.