ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.

ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes, with Rab12 playing a significant role in this process.

• Why it matters: Understanding how lysosomal stresses communicate with LRRK2 is crucial because increased LRRK2 activity is associated with Parkinson's disease risk, yet the underlying mechanisms remain unclear.
• What they did: The study used molecular and cellular approaches to show that PIKfyve inhibition promotes LRRK2 recruitment via ClC-7, which controls Rab GTPase accumulation on lysosomes, requiring Rab12 for signaling.
• The result: Findings suggest that ClC-7-dependent lysosomal remodeling and Rab accumulation are key to linking PIKfyve inhibition to LRRK2 activity, with different lysosomal stresses engaging distinct Rab and GABARAP pathways.