PFF induce LRRK2-Mediated Rab5 Phosphorylation Triggering Lysosomal Dysfunction and Neuronal Senescence [ATAC-seq]

While there is significant progress in characterizing the pathogenesis of Parkinson's disease (PD), underlying cell biological events are less well-defined. Increasing evidence suggests that endolysosomal dysfunction is a critical driver of PD pathogenesis. In this study, we explored the impact of preformed α-synuclein fibrils (PFF) on endolysosomal function and downstream events, including activation of cellular senescence pathways. We found that PFF treatment of primary cultures of mouse cortical neurons caused widespread endolysosomal dysfunction. PFF treatment also induced changes in transcriptional reprogramming and chromatin accessibility. To define underlying mechanisms we explored the status of LRRK2, finding that PFF treatment activated LRRK2 on early endosomes where it phosphorylated Rab5. PFF also induced phosphorylation of Rab7. LRRK2 activation was necessary for endolysosomal dysfunction and transcriptional changes as these changes were prevented by pharmacological inhibition of LRRK2 with MLi-2. In addition, Rab5 changes mediated by PFF treatment contributed to changes in chromatin remodeling. These cell biological insights point to a critical role in PD pathogenesis for LRRK2 activation and its engagement of the endolysosomal network and to a novel role for the LRRK2-Rab5 axis in mediating its manifestations.