Format

Send to

Choose Destination
Nat Commun. 2015 Sep 14;6:8255. doi: 10.1038/ncomms9255.

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

Choi I1,2,3, Kim B2, Byun JW1,2, Baik SH4, Huh YH5, Kim JH1,2, Mook-Jung I4, Song WK5, Shin JH6, Seo H7, Suh YH1,2,3, Jou I1,2,3, Park SM1,2,3, Kang HC8, Joe EH1,2,3,9,10.

Author information

1
Department of Biomedical Sciences, Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
2
Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
3
Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
4
Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea.
5
Bio Imaging and Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
6
Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 440-746, Korea.
7
Department of Molecular and Life Sciences, Hanyang University, Ansan 426-791, Korea.
8
Department of Physiology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
9
Department of Brain Science, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
10
Brain Disease Research Center, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.

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.

PMID:
26365310
PMCID:
PMC4647842
DOI:
10.1038/ncomms9255
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center