Genetic and Environmental Risk Factors for PSP

描述（由申请人提供）：进行性核上性麻痹（PSP）是一种病因不明的散发性脑病。H1 tau单倍型与其病因有关；然而，60%的正常对照也存在这种情况。这一点，加上较晚的症状发作，表明基因本身不会引起PSP。对环境因素假说的支持来自动物模型和观察到的PSP与暴露于线粒体复合物I抑制剂（即乙酰素）之间的关联，这些抑制剂对多巴胺能神经元具有神经毒性。PSP线粒体代谢受损和受影响脑区的氧化损伤也支持这一假设。因此，基因和环境可能单独或通过相互作用发挥作用。该应用程序将确定：1)PSP与HI/HI基因型、特定的HI亚单倍型、α -突触核蛋白多态性或帕金基因缺陷之间是否存在关联，或者是否存在基因-基因相互作用；2) PSP职业和/或环境化学品暴露之间是否存在关联，其功能或结构与鱼藤酮/醋酸原素相似；3)症状出现前的高血压或创伤性脑损伤是否与PSP相关。为了弄清PSP的复杂病因，这项病例对照多中心研究纳入了500例PSP病例、500例年龄/性别匹配的主要对照和500例次要对照进行遗传确认。以前的病例对照研究由于在规模、范围或结构上的限制而没有定论。这是第一个具有匹配对照的PSP病例系列，具有必要的基础设施来解决我们的假设并探索基因-环境相互作用。因此，它将有助于解决关于PSP病因的争议，并将激发发病机制研究和预防治疗的新途径。了解PSP的病因也可能有助于解释其他牛头病变的原因，如阿尔茨海默病。这个由运动障碍专家、流行病学家、遗传学家、生物统计学家、工业卫生学家和毒理学家组成的多学科团队非常适合解开PSP的复杂病因。使用NINDS细胞库作为基因库还将允许与其他研究人员共享DNA样本。

DESCRIPTION (provided by applicant): Progressive supranuclear palsy (PSP) is a sporadic tauopathy with unknown cause. The H1 tau haplotype is implicated in its etiology; however, it is also present in 60% of normal controls. This, coupled with late symptom onset, indicates that genetics alone does not cause PSP. Support for the environmental factor hypothesis stems from animal models and the observed association between PSP and exposure to mitochondrial complex I inhibitors (i.e., acetogenins), which are neurotoxic to dopaminergic neurons. Impaired metabolism in PSP mitochondria and oxidative injury in affected brain areas also support this hypothesis. Hence, genes and environment may both play a role either alone or through their interactions. This application will determine: 1) if there is an association between PSP and the HI/HI genotype, specific HI sub-haplotypes, alpha-synuclein polymorphisms or parkin gene deficits, or if there are gene-gene interactions; 2) if there is an association between PSP occupational and/or environmental chemical exposures functionally or structurally similar to rotenone/acetogenins; and 3) if hypertension or traumatic brain injury prior to symptom-onset is associated with PSP. To disentangle the complex etiology of PSP, this case-control multicenter study involves 500 PSP cases, 500 age/gender matched primary controls, and 500 secondary controls for genetic confirmation. Previous case-control studies have been inconclusive because of limitations in size, scope, or structure. This is the first adequately powered series of PSP cases with matched controls that has the necessary infrastructure to address our hypotheses and explore gene-environmental interactions. As a result, it will help resolve controversies concerning the cause(s) of PSP and will stimulate new avenues of pathogenesis research and prophylactic therapies. Understanding the etiology of PSP may also help explain the causes of other tauopathies such as Alzheimer's disease. This multidisciplinary team of movement disorder specialists, epidemiologists, geneticists, biostatisticians, industrial hygienist and toxicologist is well suited to unravel the complex etiology of PSP. The use of the NINDS cell repository for genetic banking will also allow DNA sample sharing with other investigators.