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

被引:247
作者
Gomez-Suaga, Patricia [1 ]
Luzon-Toro, Berta [1 ]
Churamani, Dev [2 ]
Zhang, Ling [3 ]
Bloor-Young, Duncan [4 ]
Patel, Sandip [2 ]
Woodman, Philip G. [3 ]
Churchill, Grant C. [4 ]
Hilfiker, Sabine [1 ]
机构
[1] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18100, Spain
[2] UCL, Dept Cell & Dev Biol, London, England
[3] Univ Manchester, Fac Life Sci, Manchester, Lancs, England
[4] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England
基金
英国生物技术与生命科学研究理事会;
关键词
DISEASE-ASSOCIATED MUTATIONS; ACTIVATED PROTEIN-KINASE; PARKINSONS-DISEASE; ENDOPLASMIC-RETICULUM; NEURONAL TOXICITY; ALPHA-SYNUCLEIN; LRRK2; CA2+; CELLS; BCL-2;
D O I
10.1093/hmg/ddr481
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:511 / 525
页数:15
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