α-Synuclein Induced the Occurrence of RBD via Interaction with OX1R and Modulated Its Degradation

Rapid eye movement (REM) sleep behavior disorder (RBD) is a powerful early sign of Parkinson's disease (PD), but the pathogenetic mechanism involved in RBD remains largely unexplored. alpha-Synuclein has been verified to form Lewy bodies in the orexin neurons, whose activity and function rely on the orexin 1 receptor (OX1R). Dysfunction of the OX1R may induce the occurrence of RBD. Here, we determined the role of the interaction between alpha-Synuclein and OX1R in the pathogenesis of RBD, in vitro and in vivo. We found that injection of alpha-Synuclein into the lateral hypothalamus area (LHA) damaged orexin neurons and induced the RBD-like sleep pattern, to further damage dopaminergic neurons and result in locomotor dysfunction in mice. alpha-Synuclein interacted with OX1R, promoting the degradation of OX1R through proteasomal and lysosomal pathways. In addition, overexpression of alpha-Synuclein downregulated OX1R-mediated signaling, subsequently leading to orexin neuron damage. We conclude that alpha-Synuclein induced the occurrence of RBD via interaction with OX1R and modulated its degradation. These findings provide evidence for a novel mechanism by which the association of alpha-Synuclein with OX1R was attributed to alpha-Synuclein-induced orexin neuron damage, which may be a new molecular target for an effective therapeutic strategy for RBD pathology.