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

Overview

1. Department of Neurosciences, University of California San Diego, La Jolla, CA USA
2. Department of Medicine, University of California San Diego, La Jolla, CA USA
3. Shiley Eye Institute, University of California San Diego, La Jolla, CA USA

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE294140, at NCBI GEO; found in “Data availability”

Data availability

All sequencing data generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession numbers GSE294140 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294140) (RNA-seq) and GSE294156 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294156) (ATAC-seq). Additional data supporting the findings of this study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 3 keywords, 82 references.

Cite

This paper

Zuo, X., Chen, Z., Chen, X.-Q., Guan, D., Shaw, P. X., Johnstone, A., Becker, A., Das, U., & Mobley, W. C. (2026). Preformed fibrils of α-synuclein rapidly activate LRRK2 on early endosomes, driving Rab5 phosphorylation and disrupting endolysosomal and synaptic function. NPJ Parkinson's disease, 12(1), 176. https://doi.org/10.1038/s41531-026-01382-z

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