Genetics of MPTP-Induced Parkinsonism

描述(由申请人提供)： 帕金森氏病(PD)是一种使人衰弱的神经疾病，每10万名50岁以上的人中就有20人患病。据估计，有100万美国公民患有帕金森病，其中60岁以上的成年人患帕金森病的几率为20分之一。按人均每年6000.00美元/患者的平均成本计算，该病的总成本约为60亿美元，其中85%由私人和政府保险机构承担。由于世界人口日益老龄化，在未来几十年内，患有这种疾病的人数应该会大幅增加。&gt；90%的帕金森病的病因不明。目前关于特发性帕金森病(IPD)的病因学假说表明，某些未知的环境因素与其影响的遗传易感性存在相互作用。1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)的发现为帕金森病提供了一个有用的模型，它似乎概括了人类所见疾病的病理。暴露于这种典型的“环境毒素”会导致黑质致密部(SNPC)多巴胺能神经元的选择性丧失。在小鼠身上，MPTP的作用依赖于菌株。我们利用QTL分析证明，导致菌株差异的基因位于1号染色体上。在这个染色体区域内，一个基因：谷胱甘肽-S-转移酶Pi2在外源物质的解毒途径中发挥作用。在这一应用中，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GSTp2及其相关家族成员的序列和表达在MPTP耐药和敏感品系小鼠中是否存在差异。2)检测阻断或转移GSTpi在体内外对细胞死亡的影响；3)建立小鼠实验性帕金森病鱼藤酮模型，并检测鱼藤酮是否改变了GSTp2；4)确定帕金森病患者GSTpi水平是否存在结构或表达上的差异。这项研究的结果应该有助于更好地理解实验性和可能的人类帕金森病的发病机制。将GSTp2确定为候选基因也可能导致诊断措施的确定，并指出对这种毁灭性疾病进行早期干预的潜在疗法。

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.