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RAB12-LRRK2 Complex Suppresses Primary Ciliogenesis and Regulates Centrosome Homeostasis in Astrocytes

Xingjian Li1,2, Hanwen Zhu3, Bik Tzu Huang1,4,5

  • 1Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Biorxiv : the Preprint Server for Biology
|July 29, 2024
PubMed

Insights

Researchers identified RAB12 as a key target of Leucine-rich repeat kinase 2 (LRRK2) in the brain. This interaction regulates cell structure, offering new therapeutic targets for Parkinson's disease (PD).

Area of Science:

  • Cell Biology
  • Neuroscience
  • Structural Biology

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) is implicated in Parkinson's disease (PD) through its phosphorylation of RAB GTPases.
  • The specific roles of LRRK2-phosphorylated RAB GTPases in brain function, particularly in relation to PD, are not fully understood.

Purpose of the Study:

  • To identify novel LRRK2 substrates in the brain.
  • To elucidate the function of the RAB12-LRRK2 complex in regulating ciliogenesis and centrosome homeostasis.
  • To provide structural insights into the RAB12-LRRK2 interaction for therapeutic development.

Main Methods:

  • Phosphoproteomics profiling to identify LRRK2 substrates in mouse brains.
  • Cryo-electron microscopy (Cryo-EM) to determine the structure of the RAB12-LRRK2 protein complex.
  • Genetic manipulation (gene deletion) in astrocytes to assess functional consequences.

Main Results:

  • RAB12 was identified as a direct substrate of LRRK2 in mouse brains.
  • The RAB12-LRRK2 complex inhibits primary ciliogenesis and regulates centrosome homeostasis in astrocytes.
  • This regulation involves RAB10 phosphorylation and Rab interacting lysosomal protein like 1 (RILPL1) recruitment.
  • PD-linked LRRK2 mutations' effects on cilia and centrosomes were ameliorated by RAB12 deletion.

Conclusions:

  • The study reveals a novel physiological role for the RAB12-LRRK2 complex in ciliogenesis and centrosome homeostasis.
  • The elucidated structure of the RAB12-LRRK2 complex provides a basis for developing therapeutics targeting PD by modulating this interaction.

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