Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson's disease.

Journal: Journal of neuroinflammation
Published Date: Jul 19, 2025

Abstract

UNLABELLED: Microglia-mediated neuroinflammation plays a crucial role in the progression of Parkinson’s disease (PD). Dysregulation of lipid droplet homeostasis is a significant factor affecting microglial inflammatory responses, but the mechanisms underlying lipid droplet imbalance in PD are currently unclear. Here, we report a subtype of microglia characterized by high expression of long-chain acyl-CoA synthetase 1 (ACSL1) through single-nucleus RNA sequencing analysis and machine learning algorithms, linking lipid metabolism to PD neuroinflammation. The results of multiple loss- and gain-of-function experiments indicate that ACSL1 localized to the endoplasmic reticulum (ER) promotes lipid droplet accumulation to exacerbate microglial activation and dopaminergic neurons death. Mechanistically, activation of TANK-binding kinase 1 (TBK1) leads to the enrichment of ACSL1 on the endoplasmic reticulum, which generates acyl-CoA that are channelled for lipid droplet biogenesis. Additionally, high expression of ACSL1 promotes activation of TBK1 through Nrdp1-mediated K63 ubiquitination of TBK1, which triggers the amplification of the aforementioned biological effects. Moreover, NF-κB directly binds to the ACSL1 promoter and positively regulates its transcription, resulting in increased ACSL1 expression in microglia. Our findings suggest that manipulating lipid droplet biogenesis by modulating ACSL1 may be a potential strategy for treating neuroinflammation in PD patients.

Authors

  • Chunlei Han
    Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • Huizhi Wang
    Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • Moxuan Zhang
    Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • Liuliu Wu
    Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, China.
  • Anni Wang
    Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • Pengda Yang
    Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • Yuan Gao
    Engineering Research Center of EMR and Intelligent Expert System, Ministry of Education, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou Zhejiang Province, China.
  • Chaonan Zhang
    School of Mechanical Engineering and Automation, Beihang University, Beijing, 100191, China.
  • Jianing Gao
    Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • Tao Xue
    Department of Cardiothoracic Surgery, Zhongda Hospital Affiliated to Southeast University, Nanjing, China.
  • Tingting Du
    Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • Yucheng Ji
    College of Computer and Information Science , Chongqing Normal University , Chongqing, China,401331.
  • Lin Shi
    Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Shatin, China.
  • Chunkui Zhang
    Center of Cognition and Brain Science, Beijing Institute of Basic Medical Sciences, Beijing, China.
  • Renpeng Li
    Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China. renpengli1024@163.com.
  • Yilei Xiao
    Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, 252000, Shandong, China. yileixiao@163.com.
  • Jianguo Zhang
    College of Automation, Harbin Engineering University, No. 145, Nantong street, Harbin, China.
  • Fangang Meng
    Department of Functional Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.

Keywords

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