星形胶质细胞激活在帕金森病神经炎症起始中的作用及机制

Neuroinflammation is one of the pathological features of Parkinson’s disease (PD) and is involved in the progressive neurodegeneration process. As the key innate immune cells of the brain, microglia are considered as the first responders to injury and initiating an inflammatory response. In the MPTP-induced PD mouse model, we found that transcriptional factor Egr-1 immediately induced in the nigral GFAP(-)/AldoC(+) astrocytes, which proceeds microglial activation. Knockout of Egr-1 not only inhibited astrocyte activation, but also significantly suppressed microglia activation, proinflammatory factors expression, lymphocyte infiltration and dopaminergic neuronal death. Thus, we propose that the induction of astroglial Egr-1 initiates the neuroinflammation of PD and promotes the dopaminergic degeneration. By using conditional Egr-1 knockout mice, translatome of specific glia cells and other methods, we propose to verify the initiating role of astroglial Egr-1 in PD neuroinflammation which will uncover the role of astrocyte activation in PD pathogenesis and provide scientific evidence for establishment of Egr-1 as a potential therapeutic target for PD.

神经免疫炎症是帕金森病(PD)的病理特征之一，参与神经元的进行性退变。作为中枢主要固有免疫细胞，小胶质细胞(MG)被认为最早感应损伤介导炎症起始。而我们在MPTP诱导的PD小鼠模型中发现，转录因子Egr-1选择性在黑质GFAP(-)/AldoC(+)星形胶质细胞(AS)中上调，时间早于MG的激活；敲除Egr-1不仅抑制了AS的激活，还显著抑制了MG激活、淋巴细胞浸润、促炎因子表达及多巴胺能(DA)神经元的死亡，提示AS在PD神经炎症发生中发挥起始作用。围绕“AS的Egr-1激活是否介导PD神经炎症起始及DA神经元死亡”这一关键科学问题，我们拟借助条件性Egr-1敲除小鼠、特定细胞(AS/MG)翻译组学鉴定等手段，获得AS中Egr-1介导PD神经炎症起始的可靠证据，明确AS在PD神经炎症/DA神经元死亡中的起始作用及机制，为以Egr-1为靶抗炎治疗PD提供科学依据。

帕金森病（parkinson’s disease, PD）是全球第二大神经退行性疾病，黑质多巴胺能（dopaminergic neuron，DAN）神经元丢失和胶质细胞激活是其主要病理特征，目前尚无有效阻止疾病进展的治疗策略。细胞类型以及脑区特异的基因表达谱有助于阐明PD新机制，寻找治疗新靶点。本项目采用核糖体亲和纯析（Translating Ribosome affinity purfication，TRAP）技术，在PD的MPTP模型中富集DAN、MG和AS的mRNA并进行RNA-Seq分析。通过DAN转录组分析，我们源头发现鞘糖脂生物合成通路在PD小鼠DAN显著下调。ST8Sia6是鞘糖脂合成通路中的关键酶，我们结果显示其在PD小鼠及PD患者DAN中表达下调。选择性在PD小鼠DAN中过表达ST8Sia6抑制神经炎症及保护DAN神经元。通过比较不同脑区（黑质和纹状体）中两种胶质细胞（小胶和星胶）在PD时的表达谱，我们发现黑质小胶质细胞是免疫反应最剧烈的细胞类型。上游调控因子预测分析显示EIF2AK2 即在DAN中发挥促死作用，又在胶质细胞中发挥促炎作用。以上研究提示DAN中鞘糖脂代谢通路异常参与DNA神经元死亡及神经免疫炎症，EIF2AK2可能是一个DAN和胶质细胞共同的上游因子介导PD病理。