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University of Virginia

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logo for University of VirginiaCenter for the Study of Neurodegenerative Diseases
Department of Neurology

Progress Report 2002-2003
The major hypothesis of our research is that mitochondrial genomic defects (e.g., mutations, deletions) are primarily causal for bioenergetic deficiencies and increased oxidative stress that leads to protein damage/aggregation and accelerated cell death in Parkinson's disease (PD). Over the last year we have made progress in the following areas.

  1. Confirming the identity of Lewy bodies in PD cybrids. By EM analysis of fibrils and further immunocytochemistry we conclude that PD cybrids make true Lewy bodies that recapitulate multiple essential characteristics of Lewy bodies found in PD nigra. PD cybrids make Lewy bodies over months in culture, and those cell lines making the most Lewy bodies have the lowest complex I activities. These findings show that PD mitochondrial gene expression in a cybrid model reproduces this essential neuropathological inclusion "spontaneously" without the need for exogenous protein expression or the inhibition of proteasomal or mitochondrial functions. Immunoprecipitant studies with antibodies against -synucelin, ubiquitin, or nitrotyrosine show that PD cybrids and PD frontal cortex show similar patterns, providing clues as to Lewy body origins.
  2. Defining the causal mitochondrial DNA (mtDNA) mutations in PD: We have finished intensive sequencing of more than 12 million bases in all seven complex I genes in six PD and six CTL frontal cortex homogenates. This represents the largest sequencing effort to date in the complex I genes. We found extensive low-level heteroplasmic mutational burdens in both PD and CTL samples that were not significantly different from each other in total number. A preliminary clustering/artificial intelligence algorithm carried out by BIOMIND, Inc., which groups mutations into randomly sized gene segments based on mutational load, reveals stretches of elevated mutations in ND2, ND4L, and ND5 genes in PD samples. No comparable regions could be found in CTL samples. Thus, our findings support the existence of extensive heteroplasmic mtDNA mutations in brain, reject the hypothesis that PD is simply an increase in age-related overall mtDNA mutational burden, and show that an analysis of sequencing data will require sophisticated bioinformatics approaches to discern differences between PD and CTL samples.
  3. Removing and replacing the human mitochondrial genome. We have developed and continue to refine molecular methods to remove ("Mitoclean") and replace ("Mitofection") the entire human mitochondrial genome. The goals of these technologies are to develop mitochondrial gene replacement as a primary treatment of sporadic neurodegenerative diseases and to demonstrate causality of mitochondrial gene mutations in PD and related diseases.
  4. Expression of mtDNA haplotypes in cybrids. In collaboration with the Duke Udall Center, we are characterizing cybrids made from PD and CTL subjects carrying various mitochondrial haplogroups, some of which are associated with the increased risk of PD.

Contact Information

University of Virginia Health System
P.O. Box 800394
Charlottesville, VA 22908
434-924-8374 (phone)
434-982-1726 (fax)


James P. Bennett, Jr., M.D., Ph.D. (bennett@virginia.edu)
W. Davis Parker, Jr., M.D. (dp8m@virginia.edu)
Patricia A. Trimmer, Ph.D. (pat5q@virginia.edu)
Jeremy B. Tuttle, Ph.D. (tuttle@virginia.edu)
G. Frederick Wooten, M.D. (gfw4b@virginia.edu)

Last updated July 08, 2008