MGH/MIT PARKINSONS DISEASE RESEARCH CENTER

根据RFA NS-98-001的要求提交，该中心将研究 α-突触核蛋白的转运，可能涉及这两种新蛋白 (Parkin和TorsinA)，导致脑内多巴胺神经元死亡。 帕金森氏症。我们还将研究基底神经节的性质。 帕金森氏症引起的功能障碍，我们将使用这些技术 用来验证我们的分子机制模型。四个项目 将涉及两个核心。第一个项目，在布拉德利博士的领导下 Hyman将确定α-突触核蛋白在路易体形成中的作用 使用转基因动物和共聚焦显微镜。第二次是在马多夫博士的领导下。 Xandra Breakefield将利用分子生物学技术确定 α-突触核蛋白基因的不同等位基因的程度， Parkin，TorsinA，在早发性扭转肌张力障碍中突变，以及 对于快速发作的发育迟缓帕金森综合征 易患帕金森氏症。第三个项目，在约翰博士的领导下 Penney将确定最脆弱的多巴胺神经元是否是 那些承担着最高负担的潜在致病 应用双标记原位杂交和反义RNA检测分子 技巧。由Ann Graybiel博士主持的第四个项目将侧重于 确定帕金森综合症的神经系统后果和阿尔法- 用四极管技术研究实验动物的突触核蛋白和肌张力障碍突变 录音。这些项目是高度集成的，每个项目都相互作用 广泛地与所有其他人一起为整个计划做出贡献。这个 该中心将由一个行政核心和一个至关重要的培训提供支持 和临床核心，将为下一步提供极好的培训场所 一代帕金森氏症研究人员。最后，两位 参与的机构确保该中心将在一个高度 支持性的环境。

Submitted in response to RFA NS-98-001 this center will study how aberrant trafficking of alpha-synuclein, which may involve the two novel proteins (parkin and torsinA), leads to the death of dopamine neurons in Parkinson's disease. We will also study the nature of the basal ganglia dysfunction caused by parkinsonism and we will use the techniques so developed to validate our models of molecular mechanisms. Four projects and two cores will be involved. The first project, under Dr. Bradley Hyman, will determine the role of alpha-synuclein in Lewy body formation using transgenic animals and confocal microscopy. The second, under Dr. Xandra Breakefield, will use molecular biological techniques to determine the degree to which different alleles of the genes for alpha-synuclein, parkin, torsinA, which is mutated in early onset torsion dystonia, and that for Rapid Onset Dystonia Parkinsonism contribute to the susceptibility to Parkinson's disease. The third project, under Dr. John Penney, will determine if the most vulnerable dopamine neurons are the ones that bear the highest burden of these potentially pathogenic molecules using double-label in situ hybridization and antisense RNA techniques. The fourth project, under Dr. Ann Graybiel, will focus on determining the neural systems consequences of parkinsonism and the alpha- synuclein and dystonia mutations in experimental animals using tetrode recordings. The projects are highly integrated, each interacting extensively with all the others to contribute to the overall program. The center will be supported by an administrative core and a vital, training and clinical core that will provide a superb training ground for the next generation of parkinson's disease researchers. Finally, the two institutions involved ensure that the center will exist in a highly supportive environment.