Parkinson's disease (PD) involves pathological loss of neurons. The long-term objective of thisresearch in our laboratory is to understand how environmental and genetic neurotoxic agents interact tosignal and regulate the survival/apoptosis machinery in PD pathogenesis. Mitochondrial dysfunction hasbeen propsoed as a key mechanism that mediates demise of dopamingergic neurons in PD. However, thedetailed molecular mechanisms by which PD relevant environmental toxicants affect mitochondria!transcription and activity remain unknown. Our recently published findings highlight the key role.of nucleartranscription factor myocyte enhancer factor 2 (MEF2) in neuronal survival. Our unpublished studies haverevealed unexpected presence and function of MEF2 in mitochondria. Based on this, we propose to explorethe role of mitochondrial MEF2 in mediating and integrating the toxic signals of PD relevant environmentaltoxicants in the degeneration of dopamine neurons. We propose to: I. Determine the role of mitochondrialMEF2 in regulating transcription of mitochondrial genome in dopaminergic neurons; II. Study theregulation of mitochondrial MEF2 by PD relevant environmental toxicants in mitochondrialdysfunction and neuronal death in cellular models; and III. Establish the regulation and function ofmitochondrial MEF2 in toxicant-induced animal models of PD. To accomplish aim l-lll, we will establishthe role of MEF2 in mitochondrial gene transcription in dopaminergic neuronal cell line SN4741 cells andprimary neurons and test a group of model toxicants including MPP+(metabolite of MPTP) and rotenone incellular and rodent modeis to investigate whether de-regulation of mitochondrial MEF2 mediates the toxiceffects of these toxins. We will attempt to extend our findings to PD patients by correlating the levels andactivit of mitochondrial MEF2 with the disease. We will use a combination of morphological, biochemical,functional and genetic methods in the proposed study. These studies will allow us to assess whethertargeting mitochondrial MEF2 underlies environmental toxicant-induced apoptosis of dopamine neurons.The novel insight gained from this study will demonstrate how environmental toxicants may disruptmitochondrial function, providing a molecular explanation for the loss of dopamine neurons that mayrelevant to both sporadic and familial PD and a potential therapeutic target.
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