LRRK2, lysosome damage, and Parkinson's disease

Abstract

Limited understanding of regulatory mechanisms controlling LRRK2 kinase activity has hindered insights into both its normal biology and how its dysregulation contributes to Parkinson's disease. Fortunately, recent years have yielded an increased understanding of how LRRK2 kinase activity is dynamically regulated by recruitment to endolysosomal membranes. Notably, multiple small GTPases from the Rab family act as both activators and substrates of LRRK2. Additionally, it was recently discovered that LRRK2 is recruited to, and activated at, stressed or damaged lysosomes through an interaction with GABARAP via the CASM (conjugation of ATG8 to single membranes) pathway. These discoveries position LRRK2 within the rapidly growing field of lysosomal damage and repair mechanisms, offering important insights into lysosome biology and the pathogenesis of Parkinson's disease.