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Interaction of RAGE with α-synuclein fibrils mediates inflammatory response of microglia
Houfang Long1, Shengnan Zhang1, Shuyi Zeng2
1Interdisciplinary 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.
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.
Insights
Receptor for advanced glycation end products (RAGE) binds alpha-synuclein fibrils on microglia, driving Parkinson's disease neuroinflammation. Blocking this interaction offers a therapeutic target for neuroprotection.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Parkinson's disease (PD) involves microglia-mediated neuroinflammation and alpha-synuclein (α-syn) aggregation.
- The interaction mechanism between α-syn and microglia exacerbates neurodegeneration in PD.
- Understanding this crosstalk is crucial for developing effective therapies against α-syn-induced neuroinflammation.
Purpose of the Study:
- To elucidate the structural mechanism of α-syn fibril interaction with microglia.
- To identify the specific receptor mediating microglial inflammatory responses to α-syn.
- To explore RAGE as a potential therapeutic target for PD.
Main Methods:
- Structure-based interaction predictions.
- Nuclear magnetic resonance (NMR) spectroscopy.
- Mutagenesis studies.
- Genetic depletion of RAGE and pharmacological inhibition (FPS-ZM1).
Main Results:
- Receptor for advanced glycation end products (RAGE) identified as a microglial receptor for α-syn fibrils.
- NMR and mutagenesis confirmed binding between the RAGE V domain and acidic C-terminal residues of α-syn.
- Binding of α-syn fibrils to RAGE triggers microglial neuroinflammation.
- Genetic deletion of RAGE and FPS-ZM1 treatment blocked α-syn-induced inflammation.
Conclusions:
- RAGE plays a critical role in mediating microglial inflammatory responses to α-syn fibrils.
- The structural basis for RAGE-α-syn interaction involves specific domains and residues.
- Targeting the RAGE-α-syn pathway presents a promising therapeutic strategy for Parkinson's disease.
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