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

Microglia-mediated neuroinflammation and a-synuclein (a-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 therapeu-tic inhibition of a-syn-induced neuroinflammation. Here, we initiate from structure-based interaction predic-tions and find that receptor for advanced glycation end products (RAGE) serves as a receptor of a-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 a-syn. Further-more, the binding of a-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 mech-anism, of RAGE in mediating the inflammatory response of microglia to a-syn fibrils, which may help to estab-lish effective therapeutic strategies to alleviate a-syn-induced neuroinflammation and neuronal damage.

Automated summary

This study reveals that RAGE serves as a receptor of α-syn fibrils on microglia, and its binding with α-syn induces neuroinflammation. The structural mechanism of RAGE in mediating the inflammatory response to α-syn fibrils is validated.