Inhibition of LRRK2 kinase activity stimulates macroautophagy

Abstract

Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most important genetic contributors to Parkinson's disease. LRRK2 has been implicated in a number of cellular processes, including macroautophagy. To test whether LRRK2 has a role in regulating autophagy, a specific inhibitor of the kinase activity of LRRK2 was applied to human neuroglioma cells and downstream readouts of autophagy examined. The resulting data demonstrate that inhibition of LRRK2 kinase activity stimulates macroautophagy in the absence of any alteration in the translational targets of mTORC1, suggesting that LRRK2 regulates autophagic vesicle formation independent of canonical mTORC1 signaling. This study represents the first pharmacological dissection of the role LRRK2 plays in the autophagy/lysosomal pathway, emphasizing the importance of this pathway as a marker for LRRK2 physiological function. Moreover it highlights the need to dissect autophagy and lysosomal activities in the context of LRRK2 related pathologies with the final aim of understanding their aetiology and identifying specific targets for disease modifying therapies in patients.

Keywords: C-terminal of ROC domain; COR; DMSO; DPBS; Dimethylsulfoxide; Dulbecco's phosphate buffered saline; EDTA; Ethylene di-ammonium tetra acetic acid; LC3; LRRK2; Leucine Rich Repeat Kinase 2; Macroautophagy; Mammalian target of rapamycin; Parkinson's disease; ROC; Ras of Complex Proteins; SDS; Sodium dodecyl sulphate; WIPI2; mTOR; p62.