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LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase

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  • Insup Choi

    (Neuroscience Graduate Program, Ajou University School of Medicine
    Ajou University School of Medicine
    Chronic Inflammatory Disease Research Center, Ajou University School of Medicine)

  • Beomsue Kim

    (Ajou University School of Medicine)

  • Ji-Won Byun

    (Neuroscience Graduate Program, Ajou University School of Medicine
    Ajou University School of Medicine)

  • Sung Hoon Baik

    (College of Medicine, Seoul National University)

  • Yun Hyun Huh

    (Bio Imaging and Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology)

  • Jong-Hyeon Kim

    (Neuroscience Graduate Program, Ajou University School of Medicine
    Ajou University School of Medicine)

  • Inhee Mook-Jung

    (College of Medicine, Seoul National University)

  • Woo Keun Song

    (Bio Imaging and Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology)

  • Joo-Ho Shin

    (Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine)

  • Hyemyung Seo

    (Hanyang University)

  • Young Ho Suh

    (Neuroscience Graduate Program, Ajou University School of Medicine
    Ajou University School of Medicine
    Chronic Inflammatory Disease Research Center, Ajou University School of Medicine)

  • Ilo Jou

    (Neuroscience Graduate Program, Ajou University School of Medicine
    Ajou University School of Medicine
    Chronic Inflammatory Disease Research Center, Ajou University School of Medicine)

  • Sang Myun Park

    (Neuroscience Graduate Program, Ajou University School of Medicine
    Ajou University School of Medicine
    Chronic Inflammatory Disease Research Center, Ajou University School of Medicine)

  • Ho Chul Kang

    (Ajou University School of Medicine)

  • Eun-Hye Joe

    (Neuroscience Graduate Program, Ajou University School of Medicine
    Ajou University School of Medicine
    Chronic Inflammatory Disease Research Center, Ajou University School of Medicine
    Ajou University School of Medicine)

Abstract

In response to brain injury, microglia rapidly extend processes that isolate lesion sites and protect the brain from further injury. Here we report that microglia carrying a pathogenic mutation in the Parkinson’s disease (PD)-associated gene, G2019S-LRRK2 (GS-Tg microglia), show retarded ADP-induced motility and delayed isolation of injury, compared with non-Tg microglia. Conversely, LRRK2 knockdown microglia are highly motile compared with control cells. In our functional assays, LRRK2 binds to focal adhesion kinase (FAK) and phosphorylates its Thr–X–Arg/Lys (TXR/K) motif(s), eventually attenuating FAK activity marked by decreased pY397 phosphorylation (pY397). GS-LRRK2 decreases the levels of pY397 in the brain, microglia and HEK cells. In addition, treatment with an inhibitor of LRRK2 kinase restores pY397 levels, decreased pTXR levels and rescued motility of GS-Tg microglia. These results collectively suggest that G2019S mutation of LRRK2 may contribute to the development of PD by inhibiting microglial response to brain injury.

Suggested Citation

  • Insup Choi & Beomsue Kim & Ji-Won Byun & Sung Hoon Baik & Yun Hyun Huh & Jong-Hyeon Kim & Inhee Mook-Jung & Woo Keun Song & Joo-Ho Shin & Hyemyung Seo & Young Ho Suh & Ilo Jou & Sang Myun Park & Ho Ch, 2015. "LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9255
    DOI: 10.1038/ncomms9255
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    Cited by:

    1. A. de Rus Jacquet & M. Alpaugh & H. L. Denis & J. L. Tancredi & M. Boutin & J. Decaestecker & C. Beauparlant & L. Herrmann & M. Saint-Pierre & M. Parent & A. Droit & S. Breton & F. Cicchetti, 2023. "The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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