Zhou Kai-Ge, Huang Yi-Bin, Zhu Zi-Wen, Jiang Ming, Jin Ling-Jing, Guan Qiang, Tian Lu-Lu, Zhang Jing-Xing
Department of Neurology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China.
School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Arch Gerontol Geriatr. 2025 Apr;131:105738. doi: 10.1016/j.archger.2024.105738. Epub 2024 Dec 31.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder marked by the progressive loss of dopamine neurons in the substantia nigra. α-synuclein (SNCA) aggregation-induced microglia activation and neuroinflammation play vital role in the pathology of PD. Our previous studies showed that mesencephalic astrocyte-derived neurotrophic factor (MANF) could inhibit SNCA accumulation and Lipopolysaccharides (LPS)-induced neuroinflammation, but the specific molecular mechanism remains unclear. In this study, we showed that knock-down the expression of MANF leads to the up-regulation of inflammatory factor tumor necrosis factor-α (TNF-α). Exogenous MANF protein inhibits LPS-induced neuroinflammation in BV2 cells. Additionally, our results indicated that knock-down of the expression of MANF triggered autophagic pathway dysfunction, while exogenous addition of MANF protein or using adeno-associated virus 8 (AAV8) mediated MANF over-expression could activate the autophagic system and subsequently suppress SNCA accumulation. Furthermore, using autophagy inhibitor to block autophagic flux, we found that MANF prevented neuroinflammation by autophagy-mediated SNCA degradation. Collectively, this study indicated that MANF has potential therapeutic value for PD. Autophagy and its role in MANF-mediated anti-inflammatory properties may provide new sights that target SNCA pathology in PD.
帕金森病（PD）是第二常见的神经退行性疾病，其特征是黑质中多巴胺能神经元逐渐丧失。α-突触核蛋白（SNCA）聚集诱导的小胶质细胞活化和神经炎症在PD的病理过程中起着至关重要的作用。我们之前的研究表明，中脑星形胶质细胞源性神经营养因子（MANF）可以抑制SNCA的积累以及脂多糖（LPS）诱导的神经炎症，但具体的分子机制仍不清楚。在本研究中，我们发现敲低MANF的表达会导致炎症因子肿瘤坏死因子-α（TNF-α）的上调。外源性MANF蛋白可抑制BV2细胞中LPS诱导的神经炎症。此外，我们的结果表明，敲低MANF的表达会引发自噬途径功能障碍，而外源性添加MANF蛋白或使用腺相关病毒8（AAV8）介导的MANF过表达可以激活自噬系统，进而抑制SNCA的积累。此外，使用自噬抑制剂阻断自噬流，我们发现MANF通过自噬介导的SNCA降解来预防神经炎症。总的来说，本研究表明MANF对PD具有潜在的治疗价值。自噬及其在MANF介导的抗炎特性中的作用可能为针对PD中SNCA病理的治疗提供新的视角。
