Journal Article

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

Patricia Gómez-Suaga, Berta Luzón-Toro, Dev Churamani, Ling Zhang, Duncan Bloor-Young, Sandip Patel, Philip G. Woodman, Grant C. Churchill and Sabine Hilfiker

in Human Molecular Genetics

Volume 21, issue 3, pages 511-525
Published in print February 2012 | ISSN: 0964-6906
Published online October 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr481

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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 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.

Journal Article.  8878 words.  Illustrated.

Subjects: Genetics and Genomics

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