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.
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