Glucosylceramide induced ectosomes propagate pathogenic α-synuclein in Parkinson’s disease

• DOI: 10.1101/2025.02.14.638390
• Publication Date: 2025-02-16T14:25:22Z
• Authors: Julie Jacquemyn; Brian Mariott; Jinlan Chang; Nathanael Y J Lee; Luis F. Rubio Atonal; Ceili Green; Jeremy Wong; Kennedi Chik; Claudia Acevedo-M...; Carol X.-Q. Chen; Michael Nicouleau; Zhipeng You; Eric Deneault; Narges Abdian; Thomas M. Durcan; Jesse Jackson; Maria S. Ioannou

Intercellular transmission of α-synuclein contributes to Parkinson's disease pathology. Yet, the mechanisms spread are not fully understood. Here, we used live-cell microscopy examine impact associated lipid alterations on release. We discovered that increased glucosylceramides induce ectosome shedding from primary neurons, and dopaminergic neurons derived patient iPSCs harboring mutations in GBA1 (N370S, L444P W378G) LRRK2 (G2019S R1441H) compared their isogenic control. show elevated glucosylceramide similarly increases vesicle release uptake by other living mouse brains using 2-photon microscopy. Finally, ectosomes loaded with pathogenic lead pathology neighbouring neurons. These data reveal as predominant route for can only be appreciated imaging technologies.