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LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase.

Authors
Choi, I | Kim, B | Byun, JW | Baik, SH | Huh, YH | Kim, JH | Mook-Jung, I | Song, WK | Shin, JH | Seo, H | Suh, YH | Jou, I  | Park, SM  | Kang, HC  | Joe, EH
Citation
Nature communications, 6. : 8255-8255, 2015
Journal Title
Nature communications
ISSN
2041-1723
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.
MeSH

DOI
10.1038/ncomms9255
PMID
26365310
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
Ajou Authors
강, 호철  |  박, 상면  |  조, 은혜  |  주, 일로
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