Genetics of MPTP-Induced Parkinsonism

描述（由申请人提供）： 帕金森病（PD）是一种使人衰弱的神经系统疾病，每10万名50岁以上的人中有20人发病。据估计，有100万美国公民患有PD，60岁以上的成年人有1/20的机会患PD。在平均每人每年花费6000美元/患者的情况下，该疾病的总花费约为60亿美元，其中85%由私人和政府保险机构承担。由于世界人口正在逐渐老龄化，在今后几十年内，患这种疾病的人数将大幅增加。>90%的PD病例的原因不明。目前关于特发性PD（IPD）病因学的假设表明，一些未知的环境因素与遗传易感性相互作用。1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）的发现提供了一种有用的帕金森病模型，它似乎概括了人类帕金森病的病理学特征，暴露于这种典型的“环境毒素”可导致黑质黑部多巴胺能神经元（SNpc）的选择性丧失。在小鼠中，MPTP的作用是应变依赖性的。我们已经使用了QTL分析，以证明潜在的应变差异的基因位于染色体1。在该染色体区域内，一个基因：谷胱甘肽-S-转移酶pi 2在外源性试剂的解毒途径内起作用。在本申请中，我们建议研究该基因及其相关家族成员的结构和功能。提出了四个具体的目标：1）确定是否有任何差异的序列和表达的GST β 2和相关家族成员在MPTP耐药和敏感品系的小鼠。2)检查在体外和体内施用MPTP后GSTpi的阻断或转移对细胞死亡的影响; 3）在小鼠中建立实验性帕金森综合征的鱼藤酮模型，并确定GSTp 2是否响应于鱼藤酮而改变; 4）确定患有帕金森病的人中GSTpi水平是否存在结构或表达差异。这项研究的结果应导致更好地了解实验和可能的人类帕金森病的发病机制。GSTp 2作为候选基因的鉴定也可能导致诊断措施的确定，并指出早期干预这种毁灭性疾病的潜在疗法。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating neurological disorder that strikes 20 per 100,000 persons greater than 50 years of age. It is estimated that 1 million US citizens have PD, with adults over 60 having a 1 in 20 chance of getting PD. At an average per capita cost of $6000.00 year/patient, the total cost of the disease approximates $6 billion dollars, of which 85% is borne to private and government insurance agencies. Since the population of the world is getting progressively older, the number of people suffering from this disease should substantially increase within the next several decades. The cause of >90% of all PD cases is unknown. Current hypotheses on the etiology of idiopathic PD (IPD) state that there is an interaction of some as yet unknown environmental agent with a genetic predisposition to its effects. The discovery of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) has provided a useful model of Parkinsonism that appears to recapitulate the pathology of the disease seen in man. Exposure to this prototypical "environmental toxin" causes a selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In mice, the effects of MPTP are strain dependent. We have used a QTL analysis to demonstrate that the gene underlying strain differences is located on chromosome 1. Within this chromosomal region, one gene: glutathione-S-transferase pi2 functions within the detoxification pathway for exogenous agents. In this application, we propose to study the structure and function of this gene and its related family members. Four specific aims are proposed: 1) Determine if there are any differences in the sequence and expression of GSTp2 and related family members in MPTP-resistant and sensitive strains of mice. 2) Examine the effects of blockade or transfer of GSTpi on cell death following administration of MPTP in vitro and in vivo; 3) Develop the rotenone model of experimental Parkinsonism in mice and determine if GSTp2 is altered in response to rotenone; 4) Determine if there are structural or expression differences in GSTpi levels in humans with Parkinson's disease. The results of this study should lead to a better understanding of the pathogenesis of experimental and possible human Parkinson's disease. This identification of GSTp2 as a candidate gene could also lead to the identification of diagnostic measures and point to potential therapies for early intervention in this devastating illness.