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bioRxiv · 10.64898/2026.05.18.726024

GLP-1 analogs restore inflammatory, mitochondrial and intercellular signaling networks in the SncaG51D/G51D knock-in mouse model of Parkinson's disease

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

Parkinsons 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.

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Vaidya, B., Li, Y., Kim, Y., Osterman, C., Revelli, J.-P., Zoghbi, H. Y.. 2026-05-19. GLP-1 analogs restore inflammatory, mitochondrial and intercellular signaling networks in the SncaG51D/G51D knock-in mouse model of Parkinson's disease. https://doi.org/10.64898/2026.05.18.726024

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