COMPLEX I IN PARKINSONS DISEASE

帕金森病中的复合体 I

• 批准号: 3415971
• 负责人: BARRY J. HOFFER
• 金额: $ 21.77万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-15 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3415971
• 关键词: Parkinson's disease; electron transport; environmental toxicology; enzyme activity; enzyme mechanism; human subject; methylphenyltetrahydropyridine; mitochondria; neural degeneration; neurotoxins; platelets

Parkinson's disease (PD) is a devastating neurodegenerative disease which affects approximately 1 million people in this country. The chief symptoms include advancing slowness of movement (bradykinesia), tremor, rigidity, and postural imbalance. PD involves degeneration of the neurons that make dopamine, a chemical necessary for normal brain function. The diagnosis is entirely clinical: there are no routine laboratory tests available that can establish the diagnosis with certainty. PD has been considered to be an acquired disorder of unknown etiology. Treatment until 1989 has been entirely symptomatic - treating the symptoms but not the root cause of the disease. Very recent research has identified an enzyme defect in platelet mitochondria of patients with Parkinson's disease. The discovery of this defect in complex I activity suggests new investigative and therapeutic strategies, but first it is important to confirm the finding in a larger number and broader range of patients. This project proposes to examine platelet mitochondrial enzyme activity in: (1) a larger group of patients with typical Parkinson's disease (Is this enzyme assay sensitive?); (2) patients with "parkinson-plus" disorders, who have similar symptoms but also additional signs of central nervous system degeneration (Is this enzyme assay specific?), (3) first degree (blood) relatives of patients with PD (Does the enzyme defect appear to be inherited via the mitochondria (maternal) or is it autosomal dominant with reduced penetrance (the trait may be inherited from either parent, but not all who inherit it get sick?)); and (4) healthy, age-matched controls. Two other enzyme activities will also be studied as a control for assessing the overall quality of the isolated platelet mitochondria. Because a large quantity of platelets is required for these special enzyme activities, these will be obtained by plateletpheresis, in which blood is removed from the body, the platelets are separated out, and the remainder of the blood is returned to the volunteer. Although platelets have not been recognized to have functional defects in patients with PD, this project will address this question by screening many patients with PD with functional tests (e.g., rate of aggregation, response to activators) performed on a small sample of peripheral blood obtained in the routine manner. This research should establish the range of complex I activity in each disorder and the sensitivity and specificity of this finding. Family studies will establish the occurrence and pattern of inheritance. Platelet functions studies will establish whether these widely-available tests could be used for screening persons at-risk or those with a questionable diagnosis. Although development of a diagnostic test would be a major clinical advance, the more important potential result of this work would be to point the way to new therapeutic strategies. Experimental therapeutics are under way in other genetic diseases to replace or stimulate defective enzymes; such a strategy could also be pursued for PD.

帕金森病是一种毁灭性的神经退行性疾病。 影响到这个国家大约100万人。酋长 症状包括进行性运动缓慢(运动迟缓)、震颤、 僵硬，姿势不平衡。帕金森病涉及脑组织退行性变 产生多巴胺的神经元，多巴胺是正常大脑所必需的化学物质 功能。诊断完全是临床上的：没有常规的 可用的实验室测试可以确定诊断为 确定无疑。帕金森病被认为是一种未知的获得性障碍 病因学。1989年以前的治疗完全是对症治疗 症状，但不是疾病的根本原因。最近的研究 已经在慢性阻塞性肺疾病患者的血小板线粒体中发现了酶缺陷 帕金森氏症。在复合体I活动中发现这一缺陷 提出了新的研究和治疗策略，但首先是 重要的是要在更大数量和更广泛的范围内确认发现 病人。该项目建议检测血小板线粒体酶。 活动范围：(1)更多典型帕金森氏症患者 疾病(这种酶检测敏感吗？)；(2)患有 “帕金森+”障碍，他们有类似的症状，但也有额外的 中枢神经系统变性的迹象(这是酶分析吗 具体？)，(3)帕金森病患者的一级(血液)亲属(是否 这种酶缺陷似乎是通过线粒体(母体)遗传的。 或者是常染色体显性遗传，外显率降低(特征可能是 从父母任何一方继承的，但不是所有继承它的人都会生病？))；以及 (4)健康、年龄匹配的对照组。另外两种酶的活性也将 作为评价隔离药材整体质量的对照研究 血小板线粒体。因为需要大量的血小板 对于这些特殊的酶活性，将通过以下方式获得 血小板减少术，血液从体内排出，即血小板 被分离出来，剩余的血液被返回到 志愿者。尽管血小板还没有被认为具有 帕金森病患者的功能缺陷，这个项目将解决这个问题 通过使用功能测试来筛查许多帕金森病患者(例如， 聚集率、对激活剂的响应)在小样本上执行 以常规方式获取的外周血液。这项研究应该 确定每种疾病的复合体I活性的范围，以及 这一发现的敏感性和特异性。家庭研究将会 确立继承的发生和模式。血小板功能 研究将确定这些广泛可用的测试是否可以使用 用于筛查高危人群或诊断有问题的人群。 尽管诊断测试的发展将是一个重要的临床 推进，这项工作更重要的潜在结果将是 为新的治疗策略指明方向。实验治疗学 在其他遗传疾病中正在进行以取代或刺激缺陷 酶；这一策略也可用于帕金森病。