An unexpected advance in the molecular pathology of Huntington disease (HD) is reported in the November issue of Nature Genetics.
HD is a neurodegenerative disorder characterized by involuntary movements, cognitive impairment progressing to dementia, and mood disturbances--these symptoms are due to extensive loss of brain neurons. The genetic defect causing HD is an expansion of an amino-acid stretch in a protein called Huntingtin and the age of onset of HD is inversely correlated with the size of the expansion.
Analysis of mutant Huntingtin protein has attracted much attention amongst researchers since its discovery in 1993. Cynthia McMurray and Roy Dyer from the Mayo Clinic in Rochester, Minnesota, now shed light on the way in which expansion leads to the disease by demonstrating that, contrary to prediction, mutant Huntingtin protein is resistant to enzymes that normally chop it up. This results in an accumulation of mutant protein in cells; the authors go on to show that the mutant protein sequesters normal Huntingtin protein, in addition to chopped-up fragments of the normal Huntingtin.
The results indicate that neurodegeneration in people with HD may be caused by the inaccessibility of vital molecules, such as normal Huntingtin, rather than the accumulation of fragments previously thought to be derived from the mutant protein.
Dr. Cynthia T. McMurray
Department of Pharmacology
Mayo Clinic and Foundation
Tel: +1 507 284 1597
Additional contact for comment on paper:
Dr. Scott O. Zeitlin
Dept. of Neuroscience
University of Virginia School of Medicine
Tel: +1 804 924 5011
(C) Nature Genetics press release.
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