LRRK2 Suppresses Lysosome Degradative Activity in Macrophages and Microglia via Transcription Factor E3 Inhibition

Variants in leucine rich repeat kinase 2 (LRRK2) that increase kinase activity confer risk for sporadic and familial forms of Parkinson’s disease. However, LRRK2-dependent cellular processes responsible for disease risk remain uncertain. Here we show that LRRK2 negatively regulates lysosome degradative activity in macrophages and microglia via a transcriptional mechanism. Depletion of LRRK2 and inhibition of LRRK2 kinase activity both enhance lysosomal proteolytic activity and increase the expression of multiple lysosomal hydrolases. Conversely, the kinase hyperactive LRRK2 G2019S Parkinson’s disease mutant suppresses lysosomal degradative activity and gene expression. We identified transcription factor E3 (TFE3) as a mediator of LRRK2-dependent control of lysosomal gene expression. LRRK2 negatively regulates both the abundance and nuclear localization of TFE3 and LRRK2-dependent changes in lysosome protein expression require TFE3. These discoveries define a mechanism for LRRK2-dependent control of lysosomes and support a model wherein LRRK2 hyperactivity increases Parkinson’s disease risk by suppressing lysosome degradative activity.