Huntington's disease is caused by a dominant gene that encodes a protein known as huntingtin. The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, that is repeated multiple times. Normal persons have a CAG repeat count of between seven and 35 repeats, while the mutated form of the gene has anywhere from 36 to 180 repeats. The mutant form of huntingtin is broken down into toxic peptides, which contribute to the pathology of the syndrome.
Previous studies on the breakdown of huntingtin focused on the protease families known as caspases and calpains. In a recent study published in July 29, 2010, issue of the journal Neuron investigators at the Buck Institute for Age Research (Novato, CA, USA) concentrated on a different group of proteolytic enzymes, the matrix metalloproteinases (MMPs).
They used a high-throughput western blot-based screen to examine 514 siRNAs targeting the repertoire of human protease genes. This screen identified 11 proteases that, when inhibited, reduced huntingtin fragment accumulation. Three of these proteases belonged to the matrix metalloproteinase (MMP) family. One family member, MMP-10, directly cleaved huntingtin and prevented cell death when knocked down in a neuron cell culture. Correspondingly, MMPs were found to be activated in HD mouse models.
"We have found a target that has known drugs for cancer treatment that could possibly have significance for HD,” said senior author Dr. Lisa Ellerby, a senior researcher at the Buck Institute for Age Research. "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. The next step in this research will be to test some of the MMP inhibitor drugs as a potential treatment in HD mouse models. We will also be crossing mice that no longer have particular MMPs with those who have HD to see what effect that has on offspring.”
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