The Baltimore Huntington's Disease (HD) Project is an integrative clinical and basic science program designed to follow the natural history of HD in a cohort of well characterized patients, and perform laboratory studies to better understand the pathophysiology of the disorder. With the recent cloning of the gene whose expanding triplet repeat causes HD, this is now an opportune time to study the cell biology and biochemistry of the gene's protein product, in order to clarify the pathophysiology. In the Longitudinal Core Study, we will follow prospectively a well characterized cohort of 150 HD patients and 40 gene negative controls, based on an epidemiologic sample, in order to determine the influences, including the length of the triplet repeat, on the rate of progression of the disorder. Patients are evaluated and followed through the Clinical Core (B) to autopsy, and their brains are accessioned and studied through the neuropathology Core (C). The Genetics Core (D) assists in diagnosis by determining the length of the triplet repeat in IT-15, the gene which causes HD, and studies other factors which may influence age of onset in HD including possible modifier genes. The Neuropsychology Project (1) will better define cognitive deficits of HD and follow their course longitudinally over time. MRI scans will be performed in the Imaging Project (2) to correlate changes in the brain with functional disability. The Cell Biology Project (3) will elucidate the basic biology of the HD protein produce. We hypothesize that the pathophysiology of the disorder arises from abnormal protein-protein interactions caused by the expanded polyglutamine tract in the HD gene product (Huntington). We will characterize the cell biology of the HD protein and identify and study the proteins with which it interacts. These studies will clarify the clinical features of HD and illuminate the basic biology of the disorder, which should contribute toward the design of rational treatment.
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