Mitochondrial Genetics and PD

这是基于我们报告的线粒体J和K单倍型群与帕金森病（PD）的显著关联，特别是它们的常见多态性A10398 G（p =约0.0001），其导致复合物I亚基ND 3中的Thr → Ala改变（货车der Walt等，2003）。相对于最常见的单倍群H，我们发现J和K单倍群以及10398 G等位基因对PD的发生具有保护作用。这一发现支持了越来越多的工作，涉及线粒体的复合物I与PD风险直接相关。我们的假设是J和K单倍群和/或10398 SNP提供了优于其他单倍群的生物学优势，降低了个体发展PD的易感性。利用成熟的胞质杂交体技术，本项目将寻求鉴定与这些单倍型群和10398相关的线粒体和复合体I中的功能变化。 多态这也应该提供洞察复合物I在PD中的作用。为此，我们汇集了三个实验室的专业知识：1）我们自己的Udall中心的临床，遗传学和表达分析，2）弗吉尼亚大学Udall中心的Jim班尼特博士实验室的细胞杂种和疾病特异性线粒体专业知识，以及3）俄勒冈州大学Rod Capaldi博士实验室的线粒体结构专业知识。我们的具体目标如下：1）从具有J、K和H线粒体单倍型的个体创建胞质杂种。2)携带不同线粒体单倍群的胞质杂种的基因表达变化。我们将首先培养J、K和H单倍群的胞质杂种， 鱼藤酮并被17 β雌二醇保护以试图鉴定反应差异3）鉴定不同胞质杂种系中线粒体和复合物I的量、功能和对氧化应激的敏感性的可能的“功能”差异，使用单克隆抗体分离功能复合物I 4）J和K单倍型的基因型分层和5）PD易感性与核编码线粒体基因的关联分析

This is based upon our report of a significant association of the mitochondrial J and K haplogroups with Parkinson Disease (PD), especially their common polymorphism A10398G (p equals approximately 0.0001), which causes a Thr--> Ala change in the complex I subunit ND3 (van der Walt et al. 2003). Relative to the most common haplogroup H, we found that the J and K haplogroups and the10398G allele provided a protective effect against developing PD. This finding supports a growing body of work that implicates complex I of the mitochondria with direct involvement in PD risk Our hypothesis is that the J and K haplogroups and/or the 10398 SNP provide a biological advantage over other haplogroups that lessens an individuals' susceptibility to develop PD. Using the well-established technique of cybrids, this project will seek to identify those functional changes in mitochondria and complex I associated with these haplogroups and the 10398 polymorphism. This should also provide insight into the role of complex I in PD. To do this, we have brought together the expertise of three laboratories: 1) the clinical, genetics and expression analyses of our own Udall center, 2) the cybrid and disease-specific mitochondrial expertise of Dr. Jim Bennett's laboratory in the Udall Center at the University of Virginia, and 3) the mitochondrial structural expertise of Dr. Rod Capaldi's laboratory at the University of Oregon. Our specific aims are as follows: 1) Creation of cybrids from individuals with J, K and H mitochondrial haplotypes. 2) Gene expression changes of cybrids carrying different mitochondrial haplogroups. We will initially grow cybrids of J, K and H haplogroups with chronic rotenone and protected by 17beta estradiol to attempt to identify response differences 3) Identifying possible "functional" differences in the amounts, the functioning and the sensitivity to oxidative stress of mitochondria and complex I in the different cybrid lines, isolating functional complex I using monoclonal antibodies 4) genotypic stratification of the J and K haplotype and 5) Association analysis for PD susceptibility with nuclear encoded mitochondrial genes.