MGH/MIT PARKINSONS DISEASE RESEARCH CENTER

作为对RFA NS-98 - 001的回应提交，该中心将研究如何异常 α-突触核蛋白的运输，这可能涉及两种新的蛋白质 （parkin和torsinA），导致多巴胺神经元死亡， 帕金森氏症。我们还将研究基底神经节的性质 帕金森综合征引起的功能障碍，我们将使用这些技术， 来验证我们的分子机制模型四个项目 并且将涉及两个核心。第一个项目是由布拉德利博士 海曼，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，根据博士。 Xandra Breakefield将使用分子生物学技术来确定 α-突触核蛋白基因的不同等位基因， parkin，torsinA，其在早发性扭转肌张力障碍中突变，和 对于快速发作的肌张力障碍性帕金森症， 易患帕金森病第三个项目，在约翰博士的领导下， Penney博士将确定最脆弱的多巴胺神经元是否是 这些潜在致病性疾病的负担最重 使用双标记原位杂交和反义RNA的分子 技术.第四个项目由安·格雷比尔博士领导，将侧重于 确定帕金森症和阿尔法的神经系统后果， 使用四极管的实验动物中的突触核蛋白和肌张力障碍突变 录音.这些项目高度集成，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。的 该中心将得到一个行政核心和一个重要的培训中心的支持。 和临床核心，将提供一个极好的训练场， 帕金森病研究者的一代。最后将两 参与机构确保该中心将存在于一个高度 支持环境。

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.