2. Academic Validation
  3. Interaction of RAGE with α-synuclein fibrils mediates inflammatory response of microglia

Interaction of RAGE with α-synuclein fibrils mediates inflammatory response of microglia

  • Cell Rep. 2022 Sep 20;40(12):111401. doi: 10.1016/j.celrep.2022.111401.
Houfang Long 1,  Shengnan Zhang 1,  Shuyi Zeng 2,  Yilun Tong 1,  Jun Liu 3,  Cong Liu 4,  Dan Li 5
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
  • 3 Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: liulab@sioc.ac.cn.
  • 5 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China; WLA Laboratories, World Laureates Association, Shanghai 201203, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: lidan2017@sjtu.edu.cn.
PMID: 36130498 DOI: 10.1016/j.celrep.2022.111401
Abstract

Microglia-mediated neuroinflammation and α-synuclein (α-syn) aggregation, both as pathological hallmarks of Parkinson's disease (PD), crosstalk to exacerbate degeneration of dopaminergic neurons and PD progression. However, the mechanism underlying their interaction is poorly understood, which obstructs effective therapeutic inhibition of α-syn-induced neuroinflammation. Here, we initiate from structure-based interaction predictions and find that receptor for advanced glycation end products (RAGE) serves as a receptor of α-syn fibrils on microglia. Results of nuclear magnetic resonance (NMR) spectroscopy and mutagenesis validate that the V domain of RAGE that contains an alkaline surface can bind with acidic C-terminal residues of α-syn. Furthermore, the binding of α-syn fibrils with RAGE induces neuroinflammation, which is blocked by both genetic depletion of RAGE and inhibitor FPS-ZM1. Our work shows the important role, as well as the structural mechanism, of RAGE in mediating the inflammatory response of microglia to α-syn fibrils, which may help to establish effective therapeutic strategies to alleviate α-syn-induced neuroinflammation and neuronal damage.

Keywords

CP: Neuroscience; Parkinson's disease; RAGE; microglia; neuroinflammation; α-synuclein.

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