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

G贸mez-Suaga, Patricia; Luz贸n-Toro, Berta; Churamani, Dev; Zhang, Ling; Bloor-Young, Duncan; Patel, Sandip; Woodman, Philip G; Churchill, Grant C; Hilfiker, Sabine

Human molecular genetics. 2012;21(3):511-25.

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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-尾 (CaMKK-尾)/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.

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Place of publication:
England
Volume:
21
Issue:
3
Pagination:
511-25
Digital Object Identifier:
10.1093/hmg/ddr481
Pubmed Identifier:
22012985
Pii Identifier:
ddr481
Access state:
Active

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Manchester eScholar ID:
uk-ac-man-scw:190036
Created by:
Woodman, Philip
Created:
21st March, 2013, 08:52:56
Last modified by:
Woodman, Philip
Last modified:
21st March, 2013, 08:52:56

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