Mutations in LRRK2 (leucine-rich repeat kinase 2) represent a significant component of both sporadic and familial PD (Parkinson's disease). Pathogenic mutations cluster in the enzymatic domains of LRRK2, and kinase activity seems to correlate with cytotoxicity, suggesting the possibility of kinase-based therapeutic strategies for LRRK2-associated PD. Apart from cytotoxicity, changes in autophagy have consistently been observed upon overexpression of mutant, or knockdown of endogenous, LRRK2. However, delineating the precise mechanism(s) by which LRRK2 regulates autophagy has been difficult. Recent data suggest a mechanism involving late steps in autophagic–lysosomal clearance in a manner dependent on NAADP (nicotinic acid–adenine dinucleotide phosphate)-sensitive lysosomal Ca2+ channels. In the present paper, we review our current knowledge of the link between LRRK2 and autophagic–lysosomal clearance, including regulation of Ca2+-dependent events involving NAADP.
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October 2012
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Conference Article|
September 19 2012
A link between LRRK2, autophagy and NAADP-mediated endolysosomal calcium signalling
Patricia Gómez-Suaga;
Patricia Gómez-Suaga
*Institute of Parasitology and Biomedicine ‘López-Neyra’, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18100 Granada, Spain
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Grant C. Churchill;
Grant C. Churchill
†Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U.K.
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Sandip Patel;
Sandip Patel
‡Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, U.K.
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Sabine Hilfiker
Sabine Hilfiker
1
*Institute of Parasitology and Biomedicine ‘López-Neyra’, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18100 Granada, Spain
1To whom correspondence should be addressed (emailsabine.hilfiker@ipb.csic.es).
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Publisher: Portland Press Ltd
Received:
June 06 2012
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (5): 1140–1146.
Article history
Received:
June 06 2012
Citation
Patricia Gómez-Suaga, Grant C. Churchill, Sandip Patel, Sabine Hilfiker; A link between LRRK2, autophagy and NAADP-mediated endolysosomal calcium signalling. Biochem Soc Trans 1 October 2012; 40 (5): 1140–1146. doi: https://doi.org/10.1042/BST20120138
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