LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase

被引：87

作者：

Choi, Insup ^{[1
,2
,3
]}

Kim, Beomsue ^{[2
]}

Byun, Ji-Won ^{[1
,2
]}

Baik, Sung Hoon ^{[4
]}

Huh, Hyun ^{[5
]}

Kim, Jong-Hyeon ^{[1
,2
]}

Mook-Jung, Inhee ^{[4
]}

Song, Woo Keun ^{[5
]}

Shin, Joo-Ho ^{[6
]}

Seo, Hyemyung ^{[7
]}

Suh, Young Ho ^{[1
,2
,3
]}

Jou, Ilo ^{[1
,2
,3
]}

Park, Sang Myun ^{[1
,2
,3
]}

Kang, Ho Chul ^{[8
]}

Joe, Eun-Hye ^{[1
,2
,3
,9
,10
]}

机构：

[1] Ajou Univ, Sch Med, Neurosci Grad Program, Dept Biomed Sci, Suwon 443380, Gyeonggi Do, South Korea

[2] Ajou Univ, Sch Med, Dept Pharmacol, Suwon 443380, Gyeonggi Do, South Korea

[3] Ajou Univ, Sch Med, Chron Inflammatory Dis Res Ctr, Suwon 443380, Gyeonggi Do, South Korea

[4] Seoul Natl Univ, Coll Med, Dept Biochem & Biomed Sci, Seoul 110799, South Korea

[5] Gwangju Inst Sci & Technol, Sch Life Sci, Bio Imaging & Cell Dynam Res Ctr, Gwangju 500712, South Korea

[6] Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Div Pharmacol,Dept Mol Cell Biol, Suwon 440746, Gyeonggi Do, South Korea

[7] Hanyang Univ, Dept Mol & Life Sci, Ansan 426791, South Korea

[8] Ajou Univ, Sch Med, Dept Physiol, Suwon 443380, Gyeonggi Do, South Korea

[9] Ajou Univ, Sch Med, Dept Brain Sci, Suwon 443380, Gyeonggi Do, South Korea

[10] Ajou Univ, Sch Med, Brain Dis Res Ctr, Suwon 443380, Gyeonggi Do, South Korea

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

PARKINSONS-DISEASE; TYROSINE PHOSPHORYLATION; FAK PHOSPHORYLATION; CELL-PROLIFERATION; DOMAIN; BRAIN; PHOSPHATASE; ACTIVATION; MIGRATION; PROMOTES;

D O I：

10.1038/ncomms9255

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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