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GTP binding regulates cellular localization of Parkinson's disease-associated LRRK2

Marian Blanca Ramírez1, Antonio Jesús Lara Ordóñez1, Elena Fdez1

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

Human Molecular Genetics
|April 29, 2017
PubMed

Insights

Mutations in leucine-rich repeat kinase 2 (LRRK2) link to Parkinson's disease. Pathogenic LRRK2 mutants and kinase inhibitors abnormally associate with microtubules (MTs) via increased GTP binding, impacting MT transport.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Mutations in leucine-rich repeat kinase 2 (LRRK2) are the leading genetic cause of Parkinson's disease (PD).
  • LRRK2 is known to interact with microtubules (MTs), influencing MT-mediated transport, but the specific molecular mechanisms remain unclear.

Purpose of the Study:

  • To identify the molecular determinants within LRRK2 responsible for its interaction with microtubules.
  • To elucidate the mechanism by which pathogenic LRRK2 mutants and kinase inhibitors associate with MTs.

Main Methods:

  • Investigated the localization of LRRK2 mutants and kinase-inhibited LRRK2 in relation to MTs.
  • Assessed the role of LRRK2 GTP binding and kinase activity in MT association using synthetic mutations and pharmacological inhibitors.
  • Utilized permeabilized cell assays with GTP analogs to study LRRK2-MT interactions.

Main Results:

  • Pathogenic LRRK2 mutants and pharmacologically inhibited LRRK2 relocalize to filamentous structures colocalizing with MTs.
  • This MT association is driven by increased GTP binding, not altered kinase activity.
  • Impairing GTP binding or inhibiting LRRK2 GTP binding prevents abnormal MT localization.
  • Non-hydrolyzable GTP analogs enhance LRRK2 association with MTs.

Conclusions:

  • GTP binding, rather than kinase activity, dictates the abnormal association of pathogenic LRRK2 mutants and kinase-inhibited LRRK2 with microtubules.
  • This finding provides a mechanistic understanding of LRRK2's MT interactions and their potential impact on MT-mediated transport in Parkinson's disease.

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