Vaidya, B.; Li, Y.; Kim, Y.; Osterman, C.; Revelli, J.-P.; Zoghbi, H. Y.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a prolonged prodromal stage that culminates in motor deficits. Current PD therapies primarily alleviate symptoms, underscoring the need for disease-modifying strategies. Glucagon-like peptide-1 (GLP-1) analogs showed early promise as candidate disease modifiers, but recent clinical results have been inconsistent, and their mechanism of action remains poorly defined. Here, we employed our SncaG51D/G51D knock-in mouse model to investigate the effects of subcutaneously administered GLP-1 analogs, semaglutide and lixisenatide. Both analogs reversed motor and non-motor deficits and reduced gliosis and detergent-insoluble -synuclein. Bulk and single-nuclei transcriptomics together with CellChat-based intercellular communication analysis revealed that GLP-1 analogs normalize early striatal mitochondrial and inflammatory dysregulation and restore neuregulin (NRG) and neurexin (NRXN) signaling networks to wild-type levels. Treatment was effective when initiated either before or shortly after symptom onset, defining an early therapeutic window for GLP-1 analog therapy in PD.