中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (7): 3130-3138.doi: 10.4103/NRR.NRR-D-24-01047

• 原著:退行性病与再生 • 上一篇    下一篇

神经元DJ-1调节帕金森病中小胶质细胞活化的机制

  

  • 出版日期:2026-07-15 发布日期:2026-04-01

Neuronal DJ-1 regulates microglia activation via ADAM10-mediated CX3CL1 secretion in Parkinson's disease

Aonan Zhao1, Yanfei Ding1, Min Zhong1, Mengyue Niu1, Lingbing Wang1, Yang Jiao1, *, Jun Liu1, 2, *, Yuanyuan Li1, *   

  1. 1Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to the Shanghai Jiao Tong University School of Medicine, Shanghai, China; 
    2Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China

  • Online:2026-07-15 Published:2026-04-01
  • Contact: Yuanyuan Li, MD, liyuanyuan258@126.com; Yang Jiao, MD, drjiaoyang@163.com; Jun Liu, MD, jly0520@hotmail.com.
  • Supported by:
    This study was supported by grants from the National Natural Science Foundation of China, Nos. 82471264 (to YL), 82201392 (to AZ), and 82071415 (to JL); Shanghai Rising Stars of Medical Talents Youth Development Program, No. 2023-62 (to YL); the Shanghai Municipal Health Commission Clinical Research Special Fund for the Health Industry, No. 20234Y0026 (to YL); the Shanghai Sailing Program, No. 22YF1425100 (to AZ); and the Chinese Postdoctoral Science Foundation, No. 2021M702169 (to YJ).

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摘要：

DJ-1是一种多功能蛋白，可在氧化应激调控和神经保护中发挥重要的作用。研究显示，DJ-1可通过调节神经炎症严重影响早发性帕金森病，但其具体机制尚不明确。为此，实验首先在DJ-1 敲除小鼠和 SH-SY5Y 细胞中观察到CX3CL1（分裂素样趋化因子1）表达水平显著下降，且蛋白质芯片和GEO数据库进一步证实，DJ-1敲除会下调CX3CL1及其他趋化因子（MCP-1和白细胞介素8）的表达。进一步研究表明，DJ-1敲除可减少小鼠和 SH-SY5Y 细胞中神经元内质网中ADAM10的加工，从而减少CX3CL1的分泌，进而导致小胶质细胞的异常激活，并向促炎M1表型转变，加剧神经炎症反应，而外源性CX3CL1可减轻上述作用。同时外源性CX3CL1可改善DJ-1敲除的帕金森病小鼠模型的运动功能，并促进黑质中酪氨酸羟化酶阳性神经元的存活，并减少Iba-1阳性的小胶质细胞活化。由此得出，DJ-1可通过CX3CL1抑制小胶质细胞活化，从而保护多巴胺能神经元，且靶向DJ-1/CX3CL1轴可能成为调控神经炎症和保护多巴胺能神经元的新策略。

https://orcid.org/0000-0003-4967-3890 (Yuanyuan Li); 

https://orcid.org/0000-0002-6585-4299 (Yang Jiao); 

https://orcid.org/0000-0001-8300-8646 (Jun Liu)

关键词: DJ-1, 帕金森病蛋白7, 神经元趋化因子, ADAM10/17, 内质网, 小胶质细胞, 帕金森病, 神经炎症, 免疫干预, 中枢神经系统

Abstract: DJ-1, also known as Parkinson’s disease protein 7 (PARK7), is a multifunctional protein that plays an important role in oxidative stress regulation and neuroprotection. Previous studies have shown that DJ-1 affects early-onset Parkinson’s disease by regulating neuroinflammation, but its specific mechanism remains unclear. The study investigated the role of DJ-1 in mediating microglia–neuron communication to identify potential therapeutic targets for neuroinflammation in Parkinson’s disease. In this study, we observed a significant decrease in the levels of C-X3-C motif chemokine ligand 1 (CX3CL1) in Park7 knockout mice and SH-SY5Y cells with Park7 knockdown. Protein microarray analysis and validation using GEO datasets confirmed that knockout of the Park7 gene led to downregulation of CX3CL1 and two other chemokines, namely monocyte chemoattractant protein-1 and interleukin-8. Further investigation revealed that Park7 deficiency reduced the processing of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in the neuronal endoplasmic reticulum of both mice and SH-SY5Y cells, thereby decreasing CX3CL1 secretion. This subsequently led to abnormal microglial activation, with a shift toward the proinflammatory M1 phenotype, exacerbating neuroinflammatory responses. These effects were mitigated by exogenous CX3CL1 administration. Concurrently, exogenous CX3CL1 improved motor function in Parkinson’s disease model mice with the Park7 knockout, promoting survival of tyrosine hydroxylase-positive neurons in the substantia nigra and reducing Iba-1-positive microglial activation. These findings demonstrate that DJ-1 exerts neuroprotective effects on dopaminergic neurons by suppressing microglial activation through CX3CL1 regulation, suggesting that targeting the DJ-1/CX3CL1 axis may represent a novel therapeutic strategy for modulating neuroinflammation and protecting dopaminergic neurons. 

Key words: ADAM10/17 activity, central nervous system, endoplasmic reticulum, immune intervention, microglia, neuroinflammation, neuronal chemokines, neuronal DJ-1, PARK7, Parkinson’s disease