Mechanism of brain injury by Parkinson's gene mutation

Mechanism of brain injury by Parkinson's gene mutation

In response to brain injury, microglia rapidly extend processes that isolate lesion sites and protect the brain from further injury.

Researchers report in the journal Nature Communications 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 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 ofLRRK2 may contribute to the development of PD by inhibiting microglial response to brain injury.