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Assaying the Kinase Activity of LRRK2 in vitro
06:09

Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

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LRRK2: from kinase to GTPase to microtubules and back

Marian Blanca Ramírez1, Antonio Jesús Lara Ordóñez1, Elena Fdez1

  • 1Institute of Parasitology and Biomedicine 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.

Biochemical Society Transactions
|February 17, 2017
PubMed

Insights

Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are linked to Parkinson's disease. Pathogenic LRRK2 mutants may disrupt cellular membrane trafficking identically by increasing substrate phosphorylation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are a significant cause of familial and sporadic Parkinson's disease.
  • LRRK2 is a protein kinase involved in GTP binding and hydrolysis, with its enzymatic activities altered in pathogenic mutants.

Purpose of the Study:

  • To reconcile discrepant in vitro and cellular findings regarding LRRK2 mutant activities.
  • To elucidate the cellular roles of normal and pathogenic LRRK2 in intracellular vesicular trafficking.
  • To propose a unifying hypothesis for how LRRK2 mutants affect membrane trafficking.

Main Methods:

  • Review and summarization of known alterations in the catalytic activities of distinct pathogenic LRRK2 mutants.
  • Analysis of recent studies on LRRK2 mutant activity in intact cells.
  • Formulation of a testable working hypothesis based on existing data.

Main Results:

  • In vitro studies show differential effects of LRRK2 mutants on kinase activity and GTP binding/hydrolysis.
  • Cellular studies indicate that all pathogenic LRRK2 mutants increase kinase activity towards specific substrates.
  • Existing data suggest LRRK2 regulates intracellular vesicular trafficking pathways.

Conclusions:

  • Pathogenic LRRK2 mutants may converge on a common mechanism to disrupt membrane trafficking.
  • This disruption likely involves increased phosphorylation of key substrate proteins crucial for vesicular transport.
  • Further research is needed to validate the proposed hypothesis and understand the precise cellular mechanisms involved.
Keywords:
Parkinson's diseaseRab proteinleucine-rich repeat kinasemicrotubulephosphorylationvesicle transport

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