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

Julie Jacquemyn; Brian A. Marriott; Jinlan Chang; Ehlam Iftikhar; Kennedi Chik; Nathanael Y.J. Lee; Luis Fernando Rubio-Atonal; Ceili Green; Jeremy Wong; Claudia Acevedo-Morantes; Carol X.‐Q. Chen; Michaël Nicouleau; Zhipeng You; Éric Deneault; Narges Abdian; Thomas M. Durcan; Jesse Jackson; Maria S. Ioannou

doi:10.1038/s41556-026-01871-6

Cell BiologyNature Cell BiologyFeb 12, 2026

Peer-reviewed journal article

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

Julie Jacquemyn iD, Brian A. Marriott iD, Jinlan Chang iD, Ehlam Iftikhar iD, Kennedi Chik, Nathanael Y.J. Lee iD, Luis Fernando Rubio-Atonal iD, Ceili Green, Jeremy Wong iD, Claudia Acevedo-Morantes iD, Carol X.‐Q. Chen iD, Michaël Nicouleau iD, Zhipeng You, Éric Deneault iD, Narges Abdian iD, Thomas M. Durcan iD, Jesse Jackson iD, Maria S. Ioannou iD

Abstract

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

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