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Human Peripheral Blood Neutrophil Isolation for Interrogating the Parkinson's Associated LRRK2 Kinase Pathway by Assessing Rab10 Phosphorylation
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Human Peripheral Blood Neutrophil Isolation for Interrogating the Parkinson's Associated LRRK2 Kinase Pathway by Assessing Rab10 Phosphorylation

Published on: March 21, 2020

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RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits

Antonio Jesús Lara Ordónez1, Belén Fernández1, Elena Fdez1

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

Human Molecular Genetics
|August 21, 2019
PubMed

Insights

Mutations in Leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease by affecting RAB GTPases. This study reveals LRRK2-induced deficits in centrosomal cohesion and ciliogenesis, potentially serving as biomarkers for LRRK2-related Parkinson's disease.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Mutations in Leucine-rich repeat kinase 2 (LRRK2) are a primary genetic cause of Parkinson's disease (PD).
  • LRRK2 kinase activity phosphorylates RAB GTPases, including RAB8A and RAB10.
  • Altered RAB GTPase function is implicated in cellular processes like ciliogenesis and centrosomal cohesion.

Purpose of the Study:

  • To investigate the role of LRRK2 in regulating centrosomal cohesion and ciliogenesis.
  • To determine if RAB8A and RAB10 are involved in LRRK2-mediated cellular defects.
  • To explore the potential of these cellular alterations as biomarkers for LRRK2-related PD.

Main Methods:

  • Analysis of patient-derived cells and mutant LRRK2 mouse astrocytes.
  • Assessment of phosphorylated RAB8A and RAB10 levels.
  • Evaluation of centrosomal cohesion and ciliogenesis.
  • Inhibition of LRRK2 kinase activity.

Main Results:

  • Pathogenic LRRK2 causes increased levels of phosphorylated RAB8A and RAB10 at the centrosome.
  • Both RAB8A and RAB10, along with RILPL1, are crucial for LRRK2-mediated centrosomal cohesion deficits.
  • LRRK2-induced defects in ciliogenesis correlate with elevated phospho-RAB8A and phospho-RAB10.
  • These cellular defects are observed in patient cells and mouse models and are reversible with LRRK2 inhibition.

Conclusions:

  • LRRK2 kinase activity drives centrosomal cohesion and ciliogenesis defects through the phospho-RAB8/RAB10/RILPL1 pathway.
  • These findings suggest that alterations in centrosomal cohesion and ciliogenesis are distinct cellular readouts of LRRK2 dysfunction.
  • Centrosomal cohesion and ciliogenesis may serve as valuable cellular biomarkers for LRRK2-related Parkinson's disease.

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