Familial Parkinson's Disease: Clues to Pathogenesis

描述(由申请人提供)： BWH Udall中心利用一系列实验方法，从生物物理学和动物模型到药物发现，来阐明帕金森氏症的根本原因。这项工作的最终目标是确定帕金森病的新治疗靶点，测试这些靶点的有效性，并识别在动物模型中修改这些靶点并改善疾病的类药物分子。有四个基因与罕见的遗传性疾病有关，我们的假设是，这些基因也将引导我们找到常见零星疾病的根本原因。这些基因编码以下四种蛋白质：(1)α-突触核蛋白，疾病相关路易体的纤维成分；(2)UCH-L1，参与蛋白质泛素化和/或降解的酶；(3)parkin，另一种参与蛋白质泛素化和/或降解的酶；以及(4)DJ-1，一种功能未知的蛋白质。我们中心的基本策略是确定PD突变对这些疾病的影响。将使用三种基本方法：(1)生物化学(项目1)，(2)细胞生物学(项目2)，和老鼠模型(项目3)。除了这些基础研究，BWH Udall中心拥有两个核心设施，旨在促进我们的发现转化为新的疗法。在疾病的试管模型中，高通量药物筛选核心(核心A)被用来识别逆转PD突变影响的类药物分子。这些分子将在疾病的动物模型中进行测试。为了实现这种测试的第一步，已经建立了一个用于帕金森氏症果蝇类药物化合物测试的核心设施(核心B)。

DESCRIPTION (provided by applicant): The BWH Udall Center utilizes a range of experimental approaches, from biophysics and animal modeling to drug discovery, to elucidate the underlying cause of Parkinson's disease. The ultimate goal of this work is to identify new therapeutic targets for PD, to test the validity of these targets, and to identify drug-like molecules that modify' these targets in animal models and ameliorate disease. Four genes have been linked to rare forms of inherited disease, and it is our hypothesis that these genes will lead us to the underlying cause of the common sporadic forms of disease as well. These genes encode the following four proteins: (1) a-synuclein, the fibrillar component of the disease-associated Lewy body, (2) UCH-L1, an enzyme involved in protein ubiquitination and/or degradation, (3) parkin, another enzyme involved in protein ubiquitination arid/or degradation, and (4) DJ-1, a protein of unknown function. The basic strategy of our center is to determine the effects of the PD mutations on each of these. Three basic approaches will be utilized: (1) biochemistry (project 1), (2) cell biology (project 2), and mouse modeling (project 3). In addition to these basic studies, the BWH Udall Center houses two core facilities that are intended to facilitate the translation of our discoveries into new therapeutics. A high-throughput drug screening core (core A) is utilized to identify drug-like molecules that reverse the effects of PD mutations in test-tube models of disease. Such molecules will be tested in animal models of disease. To enable the first step in such testing, a core facility for testing of drug-like compounds in Parkinsonian drosophila has been established (core B).