Rapid LRRK2 Activation Induced by α-synuclein Preformed Fibrils Triggers Rab5 Phosphorylation and Dysregulates Endolysosomal Function, Gene Expression and Synaptic Activity in Neurons

Parkinson’s disease (PD) is characterized by α-synuclein aggregation and dysfunction of the endolysosomal network (ELN), yet how aggregated α-synuclein drives neuronal pathology remains unclear. The PD-associated kinase LRRK2 has been linked to Rab-mediated membrane trafficking, but its role in endosomal regulation and downstream nuclear responses is poorly understood. Here, we show in mouse cortical neurons that preformed α-synuclein fibrils (PFF) rapidly induce recruitment and activation of LRRK2 on early endosomes, where it phosphorylates Rab5, leading to disrupted Rab5 function with changes in the Rab5 interactome and endosomal dyshomeostasis. Endolysosomal dysfunction is accompanied by extensive chromatin remodeling and transcriptional reprogramming, including suppression of neuronal gene networks and induction of senescence-like programs. 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, confirming its function as a downstream effector. The findings point to a previously unappreciated role for LRRK2 activation and induction of a LRRK2–Rab5 axis acting at the early endosome to critically mediate changes in endolysosomal dysregulation resulting in neuronal dysfunction.