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.

journal_name

Nat Commun

journal_title

Nature communications

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

doi

10.1038/ncomms9255

subject

Has Abstract

pub_date

2015-09-14 00:00:00

pages

8255

issn

2041-1723

pii

ncomms9255

journal_volume

6

pub_type

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