Environmental exposure and astrocytic senescence: novel link to PD?

描述（由申请方提供）：细胞衰老阻止外周有丝分裂感受态细胞响应各种应激源（包括内源性氧化应激）的增殖。衰老细胞表达“衰老相关分泌表型”或SASP，其涉及可引起邻近细胞变性的促炎因子的分泌。虽然外周组织中的细胞衰老最近已被证明会导致许多与年龄相关的病理学，但它是否在脑老化和神经退行性疾病中起因果作用目前尚不清楚。我们实验室的初步数据表明，星形胶质细胞衰老的诱导可能显著促进与帕金森病（PD）相关的神经退行性变，这可能是由先前与PD风险增加相关的候选环境毒物诱导的。我们建议使用两个可用的环境毒物库进行小分子筛选，以确定额外的衰老诱导剂，特别注意以前与PD风险相关的生物可利用化合物。这将成为未来研究的基础，评估筛选中鉴定的环境毒素诱导体内星形胶质细胞衰老的能力及其对PD神经病理学的贡献。基于这些数据，我们计划检验以下假设：环境因素可能部分通过诱导星形胶质细胞衰老而增加PD风险，从而影响PD相关的神经退行性变。如果正确，我们的假设有可能改变我们如何看待和治疗PD和其他相关神经系统疾病。

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.