TNFRSF10B is involved in motor dysfunction in Parkinson's disease by regulating exosomal α-synuclein secretion from microglia

A-synuclein (α-syn) is a protein associated with the pathogenesis of Parkinson's disease (PD), a neurodegenerative disease with no effective treatment. Therefore, there has been a strong drive to clarify the pathology of PD associated with α-syn. Several mechanisms have been proposed to unravel the pathological cascade of this disease, and most of them share a particular similarity: cell-to-cell communication through exosomes (EXO). Here, we show that tumor necrosis factor receptor superfamily member 10B (TNFRSF10B) promotes the secretion of α-syn-containing EXO by microglia, resulting in motor dysfunction in PD. Upregulation of TNFRSF10B predicted severer condition in PD patients. In response to α-syn preformed fibrils (PFF), the expression of TNFRSF10B was increased in microglia. PFF-treated microglia exhibited a pro-inflammatory phenotype and caused neuronal damage by secreting α-syn-containing EXO. TNFRSF10B downregulation in microglia inhibited the secretion of α-syn-containing EXO and the release of pro-inflammatory factors, and ameliorated neuronal injury. PFF induced motor dysfunction in mice, which was ameliorated by inhibiting TNFRSF10B to suppress microglia-mediated α-syn communication or by directly depleting microglia. Taken together, these results indicate that TNFRSF10B promotes neuronal injury and motor dysfunction by delivery of α-syn-containing EXO and highlight the TNFRSF10B knockdown as a potential therapeutic target in PD.