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

Author

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  • Xingjian Li

    (Icahn School of Medicine at Mount Sinai
    The First Affiliated Hospital of Guangzhou Medical University)

  • Hanwen Zhu

    (St. Jude Children’s Research Hospital
    National University of Singapore)

  • Bik Tzu Huang

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Xianting Li

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Heesoo Kim

    (Icahn School of Medicine at Mount Sinai)

  • Haiyan Tan

    (St. Jude Children’s Research Hospital)

  • Yuanxi Zhang

    (Icahn School of Medicine at Mount Sinai)

  • Insup Choi

    (Icahn School of Medicine at Mount Sinai)

  • Junmin Peng

    (St. Jude Children’s Research Hospital)

  • Pingyi Xu

    (The First Affiliated Hospital of Guangzhou Medical University)

  • Ji Sun

    (St. Jude Children’s Research Hospital
    National University of Singapore)

  • Zhenyu Yue

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

Abstract

The leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and their phosphorylation levels are elevated by Parkinson’s disease (PD)-linked mutations of LRRK2. However, the precise function of the LRRK2-regulated RAB GTPase in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brain through phosphoproteomics profiling and solve the structure of RAB12-LRRK2 protein complex through Cryo-EM analysis. Mechanistically, RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes through enhancing the phosphorylation of RAB10 and recruiting RILPL1, while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 activity. Furthermore, the ciliary and centrosome defects caused by the PD-linked LRRK2-G2019S mutation are prevented by Rab12 deletion in astrocytes. Thus, our study reveals a physiological function of the RAB12-LRRK2 complex in regulating ciliogenesis and centrosome homeostasis. The RAB12-LRRK2 structure offers a guidance in the therapeutic development of PD by targeting the RAB12-LRRK2 interaction.

Suggested Citation

  • Xingjian Li & Hanwen Zhu & Bik Tzu Huang & Xianting Li & Heesoo Kim & Haiyan Tan & Yuanxi Zhang & Insup Choi & Junmin Peng & Pingyi Xu & Ji Sun & Zhenyu Yue, 2024. "RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52723-6
    DOI: 10.1038/s41467-024-52723-6
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    References listed on IDEAS

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    1. Sebastian Schmidt & Malte D. Luecken & Dietrich Trümbach & Sina Hembach & Kristina M. Niedermeier & Nicole Wenck & Klaus Pflügler & Constantin Stautner & Anika Böttcher & Heiko Lickert & Ciro Ramirez-, 2022. "Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease," Nature Communications, Nature, vol. 13(1), pages 1-25, December.
    2. C. K. Deniston & J. Salogiannis & S. Mathea & D. M. Snead & I. Lahiri & M. Matyszewski & O. Donosa & R. Watanabe & J. Böhning & A. K. Shiau & S. Knapp & E. Villa & S. L. Reck-Peterson & A. E. Leschzin, 2020. "Structure of LRRK2 in Parkinson’s disease and model for microtubule interaction," Nature, Nature, vol. 588(7837), pages 344-349, December.
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