How Lysosome Stress Activates the Parkinson’s Disease Kinase LRRK2

Parkinson’s disease is strongly linked to overactivation of a protein called LRRK2, but what turns this kinase on inside cells has remained unclear. In this study, we show that physical stress on lysosomes acts as a powerful trigger for LRRK2 activation. When lysosomes swell due to osmotic imbalance, they recruit signaling proteins called Rabs that recruit and activate LRRK2. Other types of lysosomal damage activate LRRK2 through a complementary pathway. Together, our findings reveal how lysosomes act as stress sensors that control LRRK2 activity, helping explain how disrupted lysosome function potentially contributes to Parkinson’s disease.