Environmental exposure and astrocytic senescence: novel link to PD?

描述（由申请人提供）：细胞衰老阻止周围有丝分裂能力细胞在各种应激源（包括内源性氧化应激）下的增殖。衰老细胞表达“衰老相关分泌表型”或SASP，涉及促炎因子的分泌，可导致邻近细胞变性。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，但它是否在脑衰老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，星形细胞衰老的诱导可能对帕金森病（PD）相关的神经退行性变有重要作用，而这可能是由先前与PD风险增加有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，以确定其他衰老诱导剂，特别关注先前与PD风险相关的生物可利用化合物。这将成为未来研究评估筛选中发现的环境毒素在体内诱导星形细胞衰老的能力及其对PD神经病理学的贡献的基础。基于这些数据，我们计划验证环境因素可能通过诱导星形细胞衰老而增加PD风险的假设，而星形细胞衰老反过来又会影响PD相关的神经退行性变。如果正确的话，我们的假设有可能改变我们对帕金森病和其他相关神经系统疾病的看法和治疗方式。

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.