Journal
HUMAN MOLECULAR GENETICS
Volume 21, Issue 3, Pages 511-525Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr481
Keywords
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Funding
- FEDER
- Spanish Ministry of Science and Innovation [SAF2009-11292, 200920I126, BFU2011-29899, GREIB. PT_2011_19]
- Fondo de Investigacion Sanitaria [FIS-PI040262]
- Junta de Andalucia [CTS 6816]
- Federacion Espanola de Parkinson (FEP)
- CSIC
- Biotechnology and Biological Sciences Research Council [BB/G013721]
- Alzheimer's Research Trust and Research into Ageing (UK)
- Biotechnology and Biological Sciences Research Council [BB/G013721/1, BB/G008523/1] Funding Source: researchfish
- Medical Research Council [G0001128] Funding Source: researchfish
- BBSRC [BB/G008523/1, BB/G013721/1] Funding Source: UKRI
- MRC [G0001128] Funding Source: UKRI
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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-beta (CaMKK-beta)/ 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 Ca2+-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.
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