July 28, 2010 Scientists at the Buck Institute for Age Research have discovered that a particular family of enzymes are involved in the breakdown of proteins that modify the production of toxic fragments that lead to the pathology of Huntington's disease. These enzymes, matrix metalloproteinases (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 faculty 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 incurable progressive neurodegenerative genetic disorder which affects motor coordination and leads to cognitive decline and dementia. Symptoms usually begin to occur in middle age; patients are often totally incapacitated 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 mutation in the huntingtin gene, located on human chromosome 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 molecular activities. Dr. Ellerby said to date, scientific queries into how those fragments are cut have focused primarily on caspases, a family of intracellular proteins that mediate cell death, and calpains, enzymes regulated by the concentration of calcium ions. The Buck Institute study involved proteases, various enzymes that catalyze 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. Buck Institute researchers identified 11 proteases that, when inhibited, 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 studies with Dr. Juan Botas at Baylor College of Medicine in Houston, researchers found that homologs of MMPs suppressed HD-induced neuronal dysfunction in fruit flies. "The next step in this research will be to test some of the MMP inhibitor 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.
Other contributors to the work: Other Buck Institute researchers involved in the study include John P. Miller, Jennifer Holcomb, Juliette Gafni, Ningzhe Zhang, Cameron Torcassi and Robert E. Hughes. Juan Botas, Ismael Al-Ramahi, Maria de Haro, Eugene Kim and Mario Sanhueza from the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston, TX also contributed to the work, along with Seung Kwak of the CHDI Foundation in Princeton, NJ. The work was supported by grants from the National Institutes of Health and the CHDI Foundation.
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- John P. Miller, Jennifer Holcomb, Ismael Al-Ramahi, Maria de Haro, Juliette Gafni, Ningzhe Zhang, Eugene Kim, Mario Sanhueza, Cameron Torcassi, Seung Kwak, Juan Botas, Robert E. Hughes, Lisa M. Ellerby. Matrix Metalloproteinases Are Modifiers of Huntingtin Proteolysis and Toxicity in Huntington's Disease. Neuron, 2010; DOI: 10.1016/j.neuron.2010.06.021
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