Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson's disease.

Parkinson's disease (PD) is characterized by the aggregation of misfolded α-synuclein (α-syn) and microglial activation. Galectin-9 (Gal-9) is an immunoregulatory mediator generated by microglia. Here, we found that α-syn fibrils are internalized by microglia and processed by microglial protease AEP, generating α-syn species with enhanced seeding activity and neurotoxicity. Notably, the uptake of α-syn fibrils by microglia leads to increased expression of Gal-9, which further promotes the production of toxic α-syn species via activation of the C/EBPβ/AEP axis. Knockout of Gal-9 attenuates α-syn pathology, dopaminergic neuronal loss, and motor impairments in a mouse model induced by intrastriatal injection of α-syn PFFs. Intrastriatal injection of Gal-9 promoted PD-like phenotypes induced by α-syn PFFs. Furthermore, the detrimental effect of Gal-9 was attenuated by the knockout of AEP. These observations illustrate the key role of Gal-9 in promoting α-syn pathology and neurodegeneration via the C/EBPβ/AEP axis in PD.