Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.
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.
Institute of Parasitology and Biomedicine Lo´pez-Neyra, Consejo Superior de Investigaciones Científicas, Avda del Conocimiento s/n, 18100 Granada, Spain.
Patricia
P
Gómez-Suaga
Berta
B
Luzón-Toro
Dev
D
Churamani
Ling
L
Zhang
Duncan
D
Bloor-Young
Sandip
S
Patel
Philip G
PG
Woodman
Grant C
GC
Churchill
Sabine
S
Hilfiker
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D020013:Calcium Signaling; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008247:Lysosomes / Q000737:chemistry; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D016716:PC12 Cells; D061988:Proteasome Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats
D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D009249:NADP; C024376:NAADP; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases