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Título: | Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP |
Autor: | Gómez-Suaga, P.; Luzón-Toro, Berta CSIC; Churamani, D.; Zhang, L.; Bloor-Young, D.; Patel, S.; Woodman, P. G.; Churchill, G. C.; Hilfiker, Sabine | Fecha de publicación: | 2012 | Editor: | Oxford University Press | Citación: | Human Molecular Genetics 21: 511- 525 (2012) | Resumen: | Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause late-onset Parkinson's disease, but its physiological function has remained largely unknown. Here we report that LRRK2 activates a calcium-dependent protein kinase kinase-β (CaMKK-β)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation. Simultaneously, LRKR2 overexpression increases the levels of the autophagy receptor p62 in a protein synthesis-dependent manner, and decreases the number of acidic lysosomes. The LRRK2-mediated effects result in increased sensitivity of cells to stressors associated with abnormal protein degradation. These effects can be mimicked by the lysosomal Ca 2+-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and can be reverted by an NAADP receptor antagonist or expression of dominant-negative receptor constructs. Collectively, our data indicate a molecular mechanism for LRRK2 deregulation of autophagy and reveal previously unidentified therapeutic targets. © The Author 2011. Published by Oxford University Press. All rights reserved. | URI: | http://hdl.handle.net/10261/74152 | DOI: | 10.1093/hmg/ddr481 | Identificadores: | doi: 10.1093/hmg/ddr481 issn: 0964-6906 |
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