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Mutations in LRRK2 (leucine-rich repeat kinase 2) represent a significant component of both sporadic and familial PD (Parkinson's disease). Pathogenic mutations cluster in the enzymatic domains of LRRK2, and kinase activity seems to correlate with cytotoxicity, suggesting the possibility of kinase-based therapeutic strategies for LRRK2-associated PD. Apart from cytotoxicity, changes in autophagy have consistently been observed upon overexpression of mutant, or knockdown of endogenous, LRRK2. However, delineating the precise mechanism(s) by which LRRK2 regulates autophagy has been difficult. Recent data suggest a mechanism involving late steps in autophagic-lysosomal clearance in a manner dependent on NAADP (nicotinic acid-adenine dinucleotide phosphate)-sensitive lysosomal Ca2+ channels. In the present paper, we review our current knowledge of the link between LRRK2 and autophagic-lysosomal clearance, including regulation of Ca2+-dependent events involving NAADP.

Original publication

DOI

10.1042/BST20120138

Type

Journal article

Journal

Biochem Soc Trans

Publication Date

10/2012

Volume

40

Pages

1140 - 1146

Keywords

Autophagy, Calcium Signaling, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Lysosomes, Mutation, NADP, Parkinson Disease, Protein-Serine-Threonine Kinases