Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu, China.
MOE Key Laboratory, Soochow University, Suzhou 215123, Jiangsu, China.
Sci Adv. 2023 Oct 6;9(40):eadi8343. doi: 10.1126/sciadv.adi8343.
Neuroinflammation is a pathological change that is involved in the progression of Parkinson's disease. Dysfunction of chaperone-mediated autophagy (CMA) has proinflammatory effects. However, the mechanism by which CMA mediates inflammation and whether CMA affects microglia and microglia-mediated neuronal damage remain to be elucidated. In the present study, we found that LAMP2A, a limiting protein for CMA, was decreased in lipopolysaccharide (LPS)-treated primary microglia. Activation of CMA by the activator CA significantly repressed LPS-induced microglial activation, whereas CMA dysfunction exacerbated microglial activation. We further identified that the protein p300 was a substrate of CMA. Degradation of p300 by CMA reduced p65 acetylation, thereby inhibiting the transcription of proinflammatory factors and the activation of the NLRP3 inflammasome. Furthermore, CA pretreatment inhibited microglia-mediated inflammation and, in turn, attenuated neuronal death in vitro and in vivo. Our findings suggest repressive effects of CMA on microglial activation through the p300-associated NF-κB signaling pathway, thus uncovering a mechanistic link between CMA and neuroinflammation.
神经炎症是帕金森病进展过程中涉及的一种病理变化。伴侣介导的自噬（CMA）功能障碍具有促炎作用。然而，CMA 介导炎症的机制以及 CMA 是否影响小胶质细胞和小胶质细胞介导的神经元损伤仍有待阐明。在本研究中，我们发现 CMA 的限制蛋白 LAMP2A 在脂多糖（LPS）处理的原代小胶质细胞中减少。CMA 激活剂 CA 的激活显着抑制 LPS 诱导的小胶质细胞活化，而 CMA 功能障碍则加剧小胶质细胞活化。我们进一步鉴定出 p300 蛋白是 CMA 的底物。CMA 降解 p300 减少了 p65 的乙酰化，从而抑制了促炎因子的转录和 NLRP3 炎性体的激活。此外，CA 预处理抑制了小胶质细胞介导的炎症，并在体外和体内减轻了神经元死亡。我们的研究结果表明，CMA 通过 p300 相关的 NF-κB 信号通路对小胶质细胞活化具有抑制作用，从而揭示了 CMA 与神经炎症之间的机制联系。
