Inhibition of LRRK2 kinase activity stimulates macroautophagy
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Claudia Manzoni Adamantios Mamais Sybille Dihanich Rosella Abeti Marc PM Soutar Helene Plun-Favreau Paola Giunti Sharon Tooze Rina Bandopadhyay Patrick A LewisAbstract
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.
Journal details
Journal Biochimica et Biophysica Acta
Volume 1833
Issue number 12
Pages 2900-2910
Publication date
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Publisher website (DOI) 10.1016/j.bbamcr.2013.07.020
Europe PubMed Central 23916833
Pubmed 23916833
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