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Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.


ABSTRACT: 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-? (CaMKK-?)/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.

SUBMITTER: Gomez-Suaga P 

PROVIDER: S-EPMC3259011 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.

Gómez-Suaga Patricia P   Luzón-Toro Berta B   Churamani Dev D   Zhang Ling L   Bloor-Young Duncan D   Patel Sandip S   Woodman Philip G PG   Churchill Grant C GC   Hilfiker Sabine S  

Human molecular genetics 20111019 3


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-  ...[more]

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