Preformed fibrils of α-synuclein rapidly activate LRRK2 on early endosomes, driving Rab5 phosphorylation and disrupting endolysosomal and synaptic function.

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.