A link between LRRK2, autophagy and NAADP-mediated endolysosomal calcium signalling

Patricia Gómez-Suaga, Grant C. Churchill, Sandip Patel, Sabine Hilfiker

Research output: Contribution to journalReview articlepeer-review

19 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)1140-1146
Number of pages7
JournalBiochemical Society transactions
Volume40
Issue number5
DOIs
StatePublished - Oct 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry

Keywords

  • Calcium signalling
  • Endolysosome
  • Leucine-rich repeat kinase 2 (LRRK2)
  • Nicotinic acid-adenine dinucleotide phosphate (NAADP)
  • Parkinson's disease
  • Rab protein

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