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

Patricia Gómez-Suaga1, Berta Luzón-Toro, Dev Churamani

  • 1Institute of Parasitology and Biomedicine Lo´pez-Neyra, Consejo Superior de Investigaciones Científicas, Avda del Conocimiento s/n, 18100 Granada, Spain.

Human Molecular Genetics
|October 21, 2011
PubMed

Insights

Leucine-rich repeat kinase-2 (LRRK2) activates a pathway that increases autophagosome formation and p62 levels. This deregulation of autophagy by LRRK2 reveals new therapeutic targets for Parkinson's disease.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Neuroscience

Background:

  • Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene are linked to late-onset Parkinson's disease.
  • The precise physiological role of LRRK2 in cellular processes remains largely unelucidated.

Purpose of the Study:

  • To investigate the molecular mechanisms by which LRRK2 influences cellular pathways.
  • To identify the functional consequences of LRRK2 activity on autophagy and lysosomal function.

Main Methods:

  • Overexpression of LRRK2 in cellular models.
  • Analysis of the calcium-dependent protein kinase kinase-β (CaMKK-β)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway.
  • Assessment of autophagosome formation and p62 levels.
  • Evaluation of lysosomal acidity and function.
  • Pharmacological manipulation using nicotinic acid adenine dinucleotide phosphate (NAADP) and its antagonists.

Main Results:

  • LRRK2 overexpression activates the CaMKK-β/AMPK pathway, leading to increased autophagosome formation.
  • LRRK2 increases p62 levels in a protein synthesis-dependent manner and reduces acidic lysosome numbers.
  • LRRK2-mediated effects enhance cellular sensitivity to proteostasis-disrupting stressors.
  • Nicotinic acid adenine dinucleotide phosphate (NAADP) mimics LRRK2 effects, which are reversible with antagonists.

Conclusions:

  • LRRK2 plays a critical role in regulating autophagy through the CaMKK-β/AMPK pathway.
  • Deregulation of LRRK2 impacts lysosomal function and cellular stress response, contributing to Parkinson's disease pathogenesis.
  • The NAADP signaling pathway represents a potential therapeutic target for LRRK2-associated Parkinson's disease.

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