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RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes

Xingjian Li1,2, Hanwen Zhu3,4, Bik Tzu Huang1,5,6

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

Nature Communications
|September 29, 2024
PubMed

Insights

Parkinson's disease (PD) researchers found that RAB12 and LRRK2 protein interaction inhibits ciliogenesis and centrosome homeostasis. This discovery offers new therapeutic targets for PD by modulating this RAB12-LRRK2 interaction.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Structural Biology

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) phosphorylates RAB GTPases, with elevated levels linked to Parkinson's disease (PD).
  • The specific brain functions of LRRK2-regulated RAB GTPases are not fully understood.

Purpose of the Study:

  • Identify RAB12 as a LRRK2 substrate in the mouse brain.
  • Elucidate the structural and functional relationship between RAB12 and LRRK2.
  • Investigate the role of the RAB12-LRRK2 complex in ciliogenesis and centrosome homeostasis, and its relevance to PD.

Main Methods:

  • Phosphoproteomics profiling to identify LRRK2 substrates.
  • Cryo-electron microscopy (Cryo-EM) to determine the structure of the RAB12-LRRK2 complex.
  • Functional assays in astrocytes to assess ciliogenesis and centrosome homeostasis.
  • Genetic manipulation (Rab12 deletion) to evaluate its role in PD-linked LRRK2 mutation models.

Main Results:

  • RAB12 identified as a robust LRRK2 substrate in the mouse brain.
  • Cryo-EM analysis provided the structure of the RAB12-LRRK2 protein complex.
  • RAB12, in conjunction with LRRK2, inhibits primary ciliogenesis and regulates centrosome homeostasis in astrocytes by phosphorylating RAB10 and recruiting RILPL1.
  • RAB12 function requires direct interaction with and activity of LRRK2.
  • Deletion of Rab12 in astrocytes prevented ciliogenesis and centrosome defects caused by the PD-linked LRRK2-G2019S mutation.

Conclusions:

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

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