MITOCHONDRIAL DNA ANALYSIS IN HUNTINGTONS DISEASE

越来越多的证据表明，生物能量缺陷是 在老年神经退行性疾病发病机制中的作用 例如亨廷顿病(HD)和帕金森氏症。 尽管HD显然是一种常染色体显性遗传病，但研究发现 大多数患有青春期HD的人继承了 他们父亲的疾病不能用经典孟德尔学派来解释 遗传原理。如果HD基因的表达导致 生物能量缺陷，则同时发生母体遗传异常 线粒体dna(Mtdna)会使个体更早发病。 这种疾病的危害。 HD的发病年龄不同，取决于父母的性别 传播了基因，可能是由于母体的遗传 保护因子(由线粒体基因组编码)或印记 父系的核基因。我们建议研究前一种假设： 存在一种母系遗传的线粒体因子，当 存在于携带核HD基因的人身上，将导致 典型的成人起病HD的发展；然而，在存在 某些线粒体DNA突变，更严重的青少年发病变异 发展起来。最近在一名大型委内瑞拉人身上测试这一假说的尝试 肯德雷德的说法没有定论。 因此，我们计划确定线粒体DNA缺失是否与 患有青少年起病的HD。首先，我们将检查青少年HD脑组织 用Southern分析和高密度法检测mtDNA缺失 限制性内切酶分析。如果在大脑中发现线粒体DNA缺失 组织，然后用聚合酶链式反应方法研究外周血mtdna。 能够检测到低丰度异质性、缺失的线粒体DNA。这个 在血细胞中存在mtDNA缺失，未受影响的HD组织将 暗示这些缺陷是主要的而非次要的 先天性巨结肠的病理生理学。我们将确定mtDNA缺失是否 评价不同神经系统疾病患者对HD的特异性 疾病，包括帕金森氏病，一种神经退行性运动 线粒体功能障碍被认为在其中起作用的疾病。 此外，我们将进行定量聚合酶链式反应，以确保线粒体DNA 缺失的数量超过了预期的年龄。 将对结果进行分析，以确定线粒体DNA缺失是否 与青少年起病有关。 这项拟议的研究将阐明线粒体DNA缺失是否在其中起作用。 以确定HD的发病年龄。如果青少年发病的一个因素 HD的发病机制是明确的，延缓发病的方法可能是 发展起来的。对这一领域的研究将有助于理解 HD和帕金森病的发病机制，从而可能导致方法 预防和治疗。此外，这项研究将产生有价值的 有关线粒体DNA缺失的生理水平的信息 衰老。

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.