Environmental exposure and astrocytic senescence: novel link to PD?

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DESCRIPTION (provided by applicant): Cellular senescence prevents the proliferation of mitotically-competent cells in the periphery in response to various stressors, including endogenous oxidative stress. Senescent cells express a 'senescence- associated secretory phenotype' or SASP, involving the secretion of pro-inflammatory factors that can cause degeneration of neighboring cells. While cell senescence in peripheral tissues has recently been shown to result in a number of age-related pathologies, whether it plays a causal role in brain aging and neurodegenerative disease is currently unknown. Preliminary data from our laboratory suggests that induction of astrocytic senescence may contributes significantly to neurodegeneration associated with Parkinson's disease (PD) and that this can be induced by candidate environmental toxicants previously linked to increased risk for PD. We propose to use two available environmental toxicant libraries to perform a small molecule screen in order to identify additional senescence-inducing agents, paying particular attention to bioavailable compounds previously associated with risk for PD. This will form the basis of future studies assessing the ability of environmental toxins identified in the screen to induce astrocytic senescence in vivo and its contribution to PD neuropathology. Based on this data, we plan to test the hypothesis that environmental agents may increase risk for PD in part via induction of astrocytic senescence that can in turn impact on PD-related neurodegeneration. If correct, our hypothesis has the potential to transform how we think about and treat PD and other related neurological disorders.