Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice

Microglial activation-induced neuroinflammation is closely associated with the development of Parkinson disease (PD). Macroautophagy/autophagy regulates many biological processes, but the role of autophagy in microglial activation during PD development remains largely unclear. In this study, we showed that deletion of microglial <i>Atg5</i> caused PD-like symptoms in mice, characterized by impairment in motor coordination and cognitive learning, loss of tyrosine hydroxylase (TH) neurons, enhancement of neuroinflammation and reduction in dopamine levels in the striatum. Mechanistically, we found that inhibition of autophagy led to NLRP3 (NLR family pyrin domain containing 3) inflammasome activation <i>via</i> PDE10A (phosphodiesterase 10A)–cyclic adenosine monophosphate (cAMP) signaling in microglia, and the sequential upregulation of downstream IL1B/IL-1β in turn increased the expression of MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]), a pro-inflammatory cytokine. Inhibition of NLRP3 inflammasome activation by administration of MCC950, a specific inhibitor for NLRP3, decreased MIF expression and neuroinflammatory levels, and rescued the loss of TH neurons in the substantial nigra (SN). Interestingly, we found that serum MIF levels in PD patients were significantly elevated. Taken together, our results reveal an important role of autophagy in microglial activation-driven PD-like symptoms, thus providing potential targets for the clinical treatment of PD. <b>Abbreviations</b>: ATG: autophagy related; cAMP: cyclic adenosine monophosphate; cKO: conditional knockout; NOS2/INOS: nitric oxide synthase 2, inducible; IL1B: interleukin 1 beta; ITGAM/CD-11b: integrin alpha M/cluster of differentiation molecule 11B; MAP1LC3: microtubule-associated protein 1 light chain 3; MIF: macrophage migration inhibitory factor (glycosylation-inhibiting factor); NLRP3: NLR family pyrin domain containing 3; PBS: phosphate-buffered saline; PD: parkinson disease; PDE10A: phosphodiesterase 10A; SN: substantial nigra; TH: tyrosine hydroxylase; TNF: tumor necrosis factor; WT: wild type.

小胶质细胞激活诱导的神经炎症与帕金森病（Parkinson disease, PD）的发生发展密切相关。巨自噬（macroautophagy，以下简称自噬）调控诸多生物学过程，但自噬在PD发生进程中小胶质细胞激活过程中的作用仍不甚明确。本研究发现，小胶质细胞Atg5基因缺失可诱导小鼠出现类帕金森病表型，具体表现为运动协调与认知学习能力受损、酪氨酸羟化酶（tyrosine hydroxylase, TH）阳性神经元丢失、神经炎症加剧以及纹状体多巴胺水平降低。机制研究表明，小胶质细胞中自噬抑制可通过磷酸二酯酶10A（phosphodiesterase 10A, PDE10A）-环磷酸腺苷（cyclic adenosine monophosphate, cAMP）信号通路激活NLR家族吡啉结构域包含蛋白3（NLR family pyrin domain containing 3, NLRP3）炎症小体；下游白细胞介素1β（interleukin 1 beta, IL1B/IL-1β）依次上调后，又进一步促进促炎细胞因子巨噬细胞迁移抑制因子（macrophage migration inhibitory factor [糖基化抑制因子], MIF）的表达。通过给予NLRP3特异性抑制剂MCC950以抑制NLRP3炎症小体激活，可降低MIF表达与神经炎症水平，并挽救黑质（substantia nigra, SN）内TH阳性神经元的丢失。有趣的是，本研究还发现帕金森病患者血清中的MIF水平显著升高。综上，本研究结果揭示了自噬在小胶质细胞激活诱导的类帕金森病表型中的关键作用，为帕金森病的临床治疗提供了潜在靶点。

**缩写说明**：ATG：自噬相关基因（autophagy related）；cAMP：环磷酸腺苷（cyclic adenosine monophosphate）；cKO：条件性敲除（conditional knockout）；NOS2/INOS：诱导型一氧化氮合酶（nitric oxide synthase 2, inducible）；IL1B：白细胞介素1β（interleukin 1 beta）；ITGAM/CD-11b：整合素αM/分化簇11B（integrin alpha M/cluster of differentiation molecule 11B）；MAP1LC3：微管相关蛋白1轻链3（microtubule-associated protein 1 light chain 3）；MIF：巨噬细胞迁移抑制因子（糖基化抑制因子）（macrophage migration inhibitory factor [glycosylation-inhibiting factor]）；NLRP3：NLR家族吡啉结构域包含蛋白3（NLR family pyrin domain containing 3）；PBS：磷酸盐缓冲液（phosphate-buffered saline）；PD：帕金森病（Parkinson disease）；PDE10A：磷酸二酯酶10A（phosphodiesterase 10A）；SN：黑质（substantia nigra）；TH：酪氨酸羟化酶（tyrosine hydroxylase）；TNF：肿瘤坏死因子（tumor necrosis factor）；WT：野生型（wild type）