title: LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase.
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.
authors.affiliation: Department of Biomedical Sciences, Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
authors.forename: Insup
authors.initials: I
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
authors.forename: Beomsue
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Byun
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Baik
authors.affiliation: Bio Imaging and Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors.forename: Yun Hyun
authors.initials: YH
authors.lastname: Huh
authors.affiliation: Department of Biomedical Sciences, Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
authors.forename: Jong-Hyeon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
authors.affiliation: Bio Imaging and Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors.forename: Woo Keun
authors.initials: WK
authors.lastname: Song
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 440-746, Korea.
authors.forename: Joo-Ho
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Department of Molecular and Life Sciences, Hanyang University, Ansan 426-791, Korea.
authors.forename: Hyemyung
authors.initials: H
authors.lastname: Seo
authors.affiliation: Department of Biomedical Sciences, Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Suh
authors.affiliation: Department of Biomedical Sciences, Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
authors.forename: Ilo
authors.initials: I
authors.lastname: Jou
authors.affiliation: Department of Biomedical Sciences, Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
authors.forename: Sang Myun
authors.initials: SM
authors.lastname: Park
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
authors.forename: Ho Chul
authors.initials: HC
authors.lastname: Kang
authors.affiliation: Department of Biomedical Sciences, Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Department of Brain Science, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.|Brain Disease Research Center, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-380, Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Joe
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries; D002465:Cell Movement / Q000235:genetics*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D014945:Wound Healing / Q000235:genetics*
chemical_list: D051416:Focal Adhesion Protein-Tyrosine Kinases; C495280:LRRK2 protein, human; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases