Abstract
Parkinson’s disease (PD) is characterized by α-synuclein aggregation and perturbation of the endolysosomal network (ELN), yet the molecular mechanisms linking α-synuclein pathology to neuronal dysfunction remain unclear. Here we report that treatment of mouse cortical neurons with α-synuclein preformed fibrils (PFFs) alters lysosomal composition and impairs lysosomal function, coupled with extensive chromatin remodeling and transcriptional reprogramming, including suppression of neuronal gene networks and activation of senescence-like programs. Mechanistically, these changes are associated with rapid recruitment and activation of the PD-associated kinase LRRK2 on early endosomes, where it phosphorylates Rab5, a key early endosomal GTPase, leading to remodeling of the Rab5 interactome, altered effector engagement, and endosomal dyshomeostasis. Pharmacological inhibition of LRRK2 with MLi-2 restores Rab5 activity, lysosomal function, chromatin accessibility, gene expression, and neuronal excitability. Knockdown of Rab5 partially rescues chromatin changes, supporting its role as a downstream effector. These findings identify LRRK2 hyperactivation and the LRRK2-Rab5 axis as key mediators of PFF-induced neuronal dysfunction, highlighting early endosomes as a central platform linking endolysosomal disruption to nuclear responses and offering potential targets for therapeutic intervention in PD.
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Acknowledgements
All work was supported by grants from the Larry L. Hillblom Foundation (2019 A-006-NET) to W.C.M., the Aligning Science Across Parkinson’s initiative (ASAP-020566) to W.C.M. and by generous support from the Broetje Family Trust and The Tan Family. We wish to express our gratitude for the members of the Mobley laboratory for helpful discussions. We wish to thank Drs Wade Harper, Thomas Kirchhausen and Suzanne Pfeffer for helpful discussions.
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W.C.M. serves as a Scientific Advisory Board (SAB) member and holds stock options from Alzheon, Inc. W.C.M. also serves as an SAB member and holds stock in Acta Pharmaceuticals, Inc. He is a patent holder under the University of California San Diego and Massachusetts General Hospital concerning γ-secretase modulators licensed to Acta Pharmaceuticals, Inc. He has served as a consultant to AC Immune. W.C.M. holds a leadership position in the Trisomy 21 Research Society. He serves on committees for the Alzheimer’s Project San Diego and an NIH COBRE Grant to the University of Nebraska. W.C.M. received a royalty payment under a patent held by Stanford University licensed to Curasen. He served as a paid adviser to Kerna.
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Zuo, X., Chen, Z., Chen, XQ. et al. Preformed fibrils of α-synuclein rapidly activate LRRK2 on early endosomes, driving Rab5 phosphorylation and disrupting endolysosomal and synaptic function. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01382-z
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DOI: https://doi.org/10.1038/s41531-026-01382-z
