Accumulating evidence suggests that a bioenergetic defect plays a major role in the pathogenesis of neurodegenerative disorders of the aging population, such as Huntington's Disease (HD) and Parkinson's disease. Although HD is clearly an autosomal dominant disorder, the finding that the majority of individuals who suffer juvenile onset of HD inherited the disease from their father cannot be explained by classical mendelian genetic principles. If expression of the HD gene results in a bioenergetic defect, then simultaneous maternal inheritance of abnormal mitochondrial DNA (mtDNA) would predispose an individual to earlier onset of the disease. The differing age of onset of HD, depending on the sex of the parent that transmitted the gene, may be due either to inheritance of a maternal protective factor (encoded by the mitochondrial genome) or to imprinting of nuclear paternal genes. We propose to study the former hypothesis: that there exists a maternally inherited mitochondrial factor that, when present in a person with the nuclear HD gene, will result in the development of typical adult onset HD; however, in the presence of certain mtDNA mutations, the more severe, juvenile onset variant develops. A recent attempt to test this hypothesis in a large Venezuelan kindred was inconclusive. Therefore, we plan to determine whether mtDNA deletions are associated with juvenile onset HD. First we will examine juvenile HD brain tissue for the presence of mtDNA deletions by Southern analysis and high density restriction endonuclease analysis. If mtDNA deletions are found in brain tissue, then peripheral blood mtDNA will be studied, using PCR methods that are able to detect low abundance heteroplasmic, deleted mtDNA. The presence of deleted mtDNA in blood cells, an unaffected HD tissue would imply that such defects play a primary rather than secondary role in the pathophysiology of HD. We will determine whether the mtDNA deletions are specific for HD by evaluating patients with varied neurological disorders, including Parkinson's disease, a neurodegenerative movement disorder in which mitochondrial dysfunction is believed to play a role. In addition, we will perform quantitative PCR to ensure that mtDNA deletions are present in quantities greater than can be expected for age. Results will be analyzed to determine whether mtDNA deletions are associated with juvenile onset HD. The proposed research will clarify whether mtDNA deletions play a role in determining the age of onset of HD. If a factor for juvenile onset of HD is elucidated, methods to delay the onset of the disease may be developed. Research in this area will contribute to understanding the pathogenesis of HD and Parkinson's disease, and thus may lead to methods of prevention and treatment. In addition, this study will yield valuable information on the physiologic levels of mtDNA deletions present with aging.
