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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-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.

Original publication

DOI

10.1093/hmg/ddr481

Type

Journal article

Journal

Hum Mol Genet

Publication Date

01/02/2012

Volume

21

Pages

511 - 525

Keywords

AMP-Activated Protein Kinases, Animals, Autophagy, Calcium Signaling, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Endoplasmic Reticulum, HEK293 Cells, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Lysosomes, NADP, PC12 Cells, Proteasome Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-bcl-2, Rats