Swollen lysosomes grab Rabs for a CASM-free route to LRRK2 activation.

Swollen lysosomes activate LRRK2 kinase through Rab GTPase binding independently of the CASM pathway in response to PIKfyve inhibition.

• Why it matters: Understanding alternative activation routes of LRRK2 is crucial because its dysregulation is linked to Parkinson's disease, and current knowledge focuses on the CASM pathway. Identifying a CASM-free mechanism could reveal new therapeutic targets for modulating LRRK2 activity.
• What they did: Clegg et al. examined lysosome swelling caused by PIKfyve inhibition and found that LRRK2 relies solely on Rab GTPase binding for lysosome localization and activation, bypassing the CASM pathway.
• The result: This finding suggests that lysosome swelling can activate LRRK2 through a Rab-dependent route, providing insight into alternative pathways of kinase activation relevant to Parkinson's disease research.