Mitochondrial Proteins in Parkinson's Disease

描述(申请人提供)：越来越多的证据表明线粒体功能障碍与帕金森病(PD)的发病机制有关：平均而言，PD患者在Complex I活性方面存在适度的系统性缺陷；一个致病基因编码线粒体激酶(Pinki)；另外两个致病基因编码蛋白质(parkin和DJ-I)，这些蛋白可进出线粒体；系统性抑制线粒体的功能可准确再现PD的许多特征。 该项目汇集了4名知名研究人员-Tim Greenamre、Jun Chen、Valerian Kagan和Teresa Hastings-他们各自对PD的发病机制和线粒体在这种疾病中所起的作用感兴趣。此外，该项目的神经病理核心主任朱夏莲也对线粒体和帕金森病有兴趣和记录。 Greenamre(项目1)将研究铁是如何通过转铁蛋白和先前未知的线粒体转铁蛋白受体(TfR2)介导的新途径在帕金森病中积累的，TfR2选择性地定位于黑质多巴胺能神经元。 Kagan(项目2)正在研究α-突触核蛋白通过与线粒体阴离子磷脂-心磷脂结合而与细胞色素c相互作用的机制和结果。这种由α-核蛋白-心磷脂-细胞色素c组成的复合体可能通过一种新的过氧化物酶活性来阻止凋亡体的形成，同时也促进了氧化应激。 陈(项目3)将研究HSP27易位到线粒体的机制和相关性，以及帕金森病中Aski/JNK的凋亡途径。 黑斯廷斯(项目4)将研究线粒体硒蛋白，如谷胱甘肽过氧化物酶4和硫氧还蛋白还原酶2，在帕金森病神经退化中的作用。 这些单独的项目由两个科学核心支持。分子核心(曹国栋)将协助每个项目设计和生产用于基因过度表达或基因沉默的构建体，产生瞬时和稳定的转基因，并生产用于体内基因转移的病毒载体。由于致病机制是在项目1-4的模型系统中定义的，因此将与神经病理学核心(Charleen Chu)合作，在死后人体组织中确认它们的相关性。 通过(I)项目之间的大量科学互动；(Ii)使用一套通用的体外和活体模型系统；以及(Iii)每个项目将使用的科学核心，统一和加强了整个计划。

DESCRIPTION (provided by applicant): Increasing evidence implicates mitochondrial dysfunction in the pathogenesis of Parkinson's disease (PD): on average, PD patients have a modest, systemic defect in complex I activity; one causative gene encodes a mitochondrial kinase (PINKi); two other causative genes encode proteins (parkin & DJ-i) that traffic in and out of mitochondria; and systemic inhibition of mitochondria] function accurately reproduces many features of PD. This program brings together 4 established investigators - Tim Greenamyre, Jun Chen, Valerian Kagan and Teresa Hastings - who are each individually interested in the pathogenesis of PD and the roles that mitochondria play in this disorder. Moreover, the director of this program's neuropathology core, Charleen Chu, also has an interest and track record in mitochondria and PD. Greenamyre (Project 1) will study how iron accumulates in PD via a novel pathway mediated by transferrin and a previously unrecognized mitochondrial transferrin receptor (TfR2) that is selectively localized in substantia nigra dopaminergic neurons. Kagan (Project 2) is studying mechanisms and consequences of the interactions of alpha-synuclein with cytochrome c via binding to the mitochondrial anionic phospholipid, cardiolipin. This complex of alphasynuclein-cardiolipin-cytochrome c may prevent apoptosome formation while also promoting oxidative stress via a novel peroxidase activity. Chen (Project 3) will study mechanisms and relevance of HSP27 translocation to mitochondria and the ASKi/JNK apoptotic pathway in PD. Hastings (Project 4) will study the roles of mitochondrial selenoproteins, such as glutathione peroxidase 4 and thioredoxin reductase 2, in neurodegeneration in PD. The individual projects are supported by 2 scientific cores. The Molecular Core (Guodong Cao) will assist each project with design and production of constructs for gene overexpression or gene silencing, generation of transient and stable transfections, and production of viral vectors for in vivo gene transfer. As pathogenic mechanisms are defined in model systems in Projects 1-4, their relevance will be confirmed in postmortem human tissue in collaboration with the Neuropathology Core (Charleen Chu). The overall Program is unified and strengthened by (i) numerous scientific interactions between the projects; (ii) the use of a common set of in vitro and in vivo model systems; and (iii) the scientific cores, which will be used by each project.