Glial Involvement in REDOX Homeostasis in the Substantia Nigra

项目总结 关于胶质细胞失调和炎症在发病机制中的作用还存在争议。 帕金森病(PD)。在帕金森病患者的死后组织中发现了炎症的迹象，以及 最近的证据表明，与家族性帕金森病相关的基因突变可以影响 星形胶质细胞和小胶质细胞。这些发现与帕金森病患者中存在的人类白细胞抗原基因突变有关 导致研究人员提出了帕金森病患者炎症和神经胶质功能障碍的病因作用。 然而，对于炎症、神经胶质细胞失调和血管紧张素转换酶之间的机制联系，缺乏直接证据。 帕金森病的神经元丢失特征。 为了确定神经胶质细胞中潜在的PD相关过程的细胞自主调节因子，我们使用了一种生物信息学 鉴定富含于小鼠脑内神经胶质细胞的PD GWAs基因的策略。有趣的是，一小部分 基因在星形胶质细胞中的表达丰富。Pd连锁单核苷酸多态在一种 这些基因，CD38，与人类大脑中CD38转录表达减少~45%有关。 以前的工作已经证明了CD38在外周免疫细胞中的作用，在那里它起到调节氧化还原的作用 细胞内和细胞外的平衡；CD38在大脑中的作用直到最近 探索过了。我们实验室的初步实验表明，CD38的表达在 人和小鼠脑内星形胶质细胞的NAD/NAM平衡在CD38的不同区域被破坏 基因敲除小鼠大脑，炎症和CD38缺乏协同作用，影响运动功能。 在这里，我们建议使用CD38作为一个原型基因来了解神经胶质细胞功能障碍如何 通过研究1)CD38在维持氧化还原过程中的需求，在小鼠中上升为PD样表型 衰老小鼠的动态平衡和多巴胺能神经元的功能和活性，2)CD38在调节中的作用 3)CD38调节对多巴胺能神经元易损性的影响 两种帕金森病小鼠模型中的神经元。一个子集的实验将测试 在CD38缺陷小鼠观察到的变化中的氧化还原失调 烟酰胺核苷是一种生物可利用的NAD前体，可以预防多巴胺能氧化应激，细胞功能障碍， 和失落。总之，这些实验有可能揭示机械因素对增长的贡献 神经元易损性与神经胶质细胞功能障碍，并提供关于神经胶质细胞在维持中的作用的新信息 多巴胺能神经元在衰老和疾病中的存活。

PROJECT SUMMARY Controversies exist regarding the contribution of glial cell dysregulation and inflammation to the pathogenesis of Parkinson Disease (PD). Signs of inflammation have been detected in postmortem tissue of PD patients, and recent evidence suggests that mutations in genes associated with familial PD can influence the function of astrocytes and microglia. These findings, together with the existence of mutations in the HLA locus in PD patients, have led investigators to propose an etiological role for inflammation and glial dysfunction in PD. However, direct evidence is lacking for mechanistic links among inflammation, glial dysregulation, and the neuronal loss characteristic of PD. To identify potential cell-autonomous mediators of PD-relevant processes in glia, we used a bioinformatics strategy to identify PD GWAS genes enriched in glial cells of the mouse brain. Interestingly, a small subset of genes exhibits enrichment of expression in astrocytes. PD-linked single-nucleotide polymorphisms in one of these genes, CD38, are associated with a ~45% reduction in CD38 transcript expression in the human brain. Previous work has demonstrated a role for CD38 in peripheral immune cells, where it serves to regulate REDOX balance in both intra- and extra-cellular compartments; the roles for CD38 in the brain have only recently been explored. Preliminary experiments from our laboratory have shown that CD38 expression is enriched in astrocytes of the human and mouse brain, NAD/NAM balance is disrupted in various regions of the CD38 knockout mouse brain, and inflammation and CD38 deficiency synergistically interact to influence motor function. Here, we propose to use CD38 as a prototypical gene to understand ways in which glial dysfunction can give rise to a PD-like phenotype in mice by investigating 1) the requirement for CD38 in the maintenance of REDOX homeostasis and dopaminergic neuron function and viability in aging mice, 2) the role for CD38 in the regulation of inflammation in the substantia nigra, and 3) the impact of CD38 modulation on the vulnerability of dopaminergic neurons in two synucleinopathy mouse models of PD. A subset of experiments will test the involvement of REDOX dysregulation in the changes observed in CD38-deficient mice by determining whether provision of nicotinamide riboside, a bioavailable NAD precursor, can prevent dopaminergic oxidative stress, cell dysfunction, and loss. Altogether, these experiments have the potential to reveal mechanistic contributors to increased neuronal vulnerability with glial dysfunction and provide novel information about the roles for glia in maintaining dopaminergic neuron survival in aging and disease.