Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
Posted on 2019-02-02 - 05:00
Abstract Background Recent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset Alzheimer’s disease (LOAD). Amongst these, a polymorphism in phospholipase C-gamma 2 (PLCG2) P522R has been reported to be protective against LOAD. PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function. Methods We assessed PLCG2 distribution in human and mouse brain tissue via immunohistochemistry and in situ hybridization. We transfected heterologous cell systems (COS7 and HEK293T cells) to determine the effect of the P522R AD-associated variant on enzymatic function using various orthogonal assays, including a radioactive assay, IP-One ELISA, and calcium assays. Results PLCG2 expression is restricted primarily to microglia and granule cells of the dentate gyrus. Plcg2 mRNA is maintained in plaque-associated microglia in the cerebral tissue of an AD mouse model. Functional analysis of the p.P522R variant demonstrated a small hypermorphic effect of the mutation on enzyme function. Conclusions The PLCG2 P522R variant is protective against AD. We show that PLCG2 is expressed in brain microglia, and the p.P522R polymorphism weakly increases enzyme function. These data suggest that activation of PLCγ2 and not inhibition could be therapeutically beneficial in AD. PLCγ2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLCγ2 may be one potential therapeutic approach.
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Magno, Lorenza; Lessard, Christian; Martins, Marta; Lang, Verena; Cruz, Pedro; Asi, Yasmine; et al. (2019). Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.4387547.v1
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AUTHORS (12)
LM
Lorenza Magno
CL
Christian Lessard
MM
Marta Martins
VL
Verena Lang
PC
Pedro Cruz
YA
Yasmine Asi
MK
Matilda Katan
JB
Jamie Bilsland
TL
Tammaryn Lashley
PC
Paramita Chakrabarty
TG
Todd Golde
PW
Paul Whiting