Abstract: 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.

Key words: α-synuclein propagation, disease-modifying treatment, glucagon-like peptide-1 receptor agonists, lixisenatide, lymphocyte-activation gene 3, mitochondrial dysfunction, Parkinson’s disease