David K. Simon, PH.D., M.D.
|Title||Associate Professor of Neurology|
|Institution||Beth Israel Deaconess Medical Center|
|Address||Beth Israel Deaconess Medical Center|
330 Brookline Ave
Boston MA 02215
Available: 10/08/12, Expires: 10/07/13
Mitochondria are the “energy factories” of our cells and also a source of potentially damaging free radicals. Inherited mutations in mitochondrial DNA (mtDNA), which is inherited strictly along the maternal line, can cause various rare clinical disorders, with the brain being one of the most commonly affected organs. MtDNA mutations also may plan a role in more common disorders such as Parkinson’s disease. Somatic (acquired) mtDNA mutations may contribute to the process of aging itself. We are now studying mechanisms to eliminate mtDNA mutations from cells. To do this, we take advantage of the fact that many pathogenic mtDNA mutations are “heteroplasmic”, meaning that there is a mix of wild-type (normal) and mutant mtDNA within individual cells. We are manipulating molecular mechanisms that may contribute to selection for or against mutant mtDNA using pharmacologic and genetic strategies. Recent work on macroautophagy has identified “mitophagy” as an important mechanism for selectively eliminating dysfunctional mitochondria. We are not testing the novel hypothesis that stimulating mitophagy by inhibiting mTOR kinase activity will enhance the preferential elimination of functionally deleterious mtDNA mutations in “cybrid” (cytoplasmic hybrid) cell lines harboring a heteroplasmic mtDNA mutation that is associated with a mitochondrial disorder in humans. We predict that enhancing mitophagy will lead to preferential elimination of mitochondria (or mitochondrial fragments) that are dysfunctional, which will tend to be those with relatively greater proportions of mutant mtDNA. This will lead to a shift over time towards a lower mutational burden. Converse experiments to inhibit mitophagy may lead to increased mutation levels. We also will test the impact of enhancing mitophagy in Polg “mutator” mice that express a proofreading deficient mitochondrial DNA polymerase resulting in an accelerated age-related accumulation of somatic mtDNA mutations and a premature aging phenotype. If our hypothesis proves to be correct, then clinical testing of strategies to enhance mitophagy can be foreseen in the future to promote a shift towards lower mutational burdens in patients with genetically based mitochondrial disorders. Similar strategies may be linked to aging and age-related neurodegenerative disease such as Parkinson’s disease. Start date and time commitment are flexible for this project. This project will involve tissue culture, western blots, quantitative PCR, immunocytochemistry, mouse models, cryostat sectioning, immunohistochemistry, cloning and sequencing, densitometry, and assays for mitochondrial function and for markers of oxidative stress. Prior laboratory research experience is preferred but not required.
Available: 07/23/12, Expires: 08/31/14
Epidemiological studies indicate that physical exercise is inversely related to the risk of Parkinson's disease (PD), raising the possibility that exercise has a neuroprotective effect on the brain. Modest exercise recently has been shown to slow the premature aging phenotype in "Polg mutator mice" that express a proofreading deficient form of Polg, resulting in the accumulation of somatic mitochondrial DNA (mtDNA) mutations. Exercise in these mice improves mitochondrial function, reduces brain atrophy, and extends lifespan. Exercise induces PGC-1alpha expression in muscle, and we hypothesize that it also may have this effect in the brain. PGC-1alpha is a transcriptional coactivator that stimulates mitochondrial biogensis and enhances antioxidant defenses. PGC-1alpha activity is low in the substantia nigra in the brain at very early stages of PD. We are now analyzing the brains of those mice to determine if exercise leads to a reduction in somatic mtDNA mutation accumulation, enhanced PGC-1alpha activity, and attenuation of the dopaminergic deficits that we have identified in these mice. If our hypothesis proves to be correct, then upregulation of PGC-1alpha in the brain might provide a mechanism linking exercise to neuroprotection against PD. This project will involve cryostat sectioning, immunohistochemistry, densitometry, quantitative PCR, western blots, and mitochondrial activity assays. Prior laboratory research is helpful but not required.
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