Toxicant-induced neurotoxicity mediated by glia-neuron and gene-environment interactions in Parkinson's disease

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The long term goal of our laboratory is to study the pathogenic mechanisms induced by environmental toxicants, genetic mutations and gene-environment interactions in Parkinson’s disease (PD) with the ultimate goal of developing disease-modifying therapeutics for this brain disorder. Overall, our research projects address the following fundamental questions: 1) Gene- environment interactions: Do mutations linked to PD render dopamine neurons more susceptible to environmental toxicants? 2) Glia-neuron interactions: How do glial cells contribute to the vulnerability of dopamine neurons in PD? 3) Excessive mitochondrial fission has been demonstrated in genetic and toxicant-induced models of PD. Can mitochondrial fission and fusion be targeted for PD treatment? These research topics are currently funded by the parent grant (R35ES030523). This supplement is requested to support a summer student. In the parent grant, we hypothesized that blocking Drp1 would attenuate autophagy impairment induced by manganese (Mn). Since then, we have generated both in vitro and in vivo data to support this hypothesis. However, so far, the focus has been on neurons. Given that Mn also affects astrocytes and microglia, it is critical to also assess the effects of Mn and Drp1 in these glial cells. For this summer project, the student will use primary astrocytes and microglia from Drp1-KO mice and WT to study the effects of Mn on autophagy in these cell types and whether Drp1-KO would be protective. This study is highly relevant and complementary to the parent project. Successful completion of this study will provide preliminary data to advance the parent project to using in vivo models to further investigate these in vitro data.