摘要Glucagon-like peptide-1 receptor agonists,originally developed for the treatment of type 2 diabetes mellitus,have been suggested as a potential disease-modifying treatment for Parkinson's disease.Some clinical trials of glucagon-like peptide-1 receptor agonists have demonstrated that they can alleviate motor dysfunction and improve quality of life for patients with Parkinson's disease.However,the mechanisms underlying the neuroprotective effects of glucagon-like peptide-1 receptor agonists have yet to be elucidated.In this study,we used α-synuclein preformed fibrils to generate in vitro and in vivo models of Parkinson's disease and investigated the effects of a short-acting glucagon-like peptide-1 receptor agonist,lixisenatide,on the propagation of α-synuclein pathology.We found that lixisenatide reduced α-synuclein phosphorylation,aggregation,and propagation in cells treated with α-synuclein preformed fibrils,and that these effects were accompanied by decreased mitochondrial dysfunction and apoptosis.Additionally,lixisenatide treatment alleviated motor dysfunction and dopaminergic cell neurodegeneration 20 weeks after stereotactic injection of α-synuclein preformed fibrils into the striatum of wild-type mice.In addition,lixisenatide inhibited α-synuclein phosphorylation and seeding between neurons,mediated by neuronal lymphocyte-activation gene 3 expression.This study provides new insights into the mechanism underlying the disease-modifying effects of glucagon-like peptide-1 receptor agonists in the treatment of Parkinson's disease.