PT  - JOURNAL ARTICLE
AU  - Lorenza Magno
AU  - Christian B Lessard
AU  - Marta Martins
AU  - Pedro Cruz
AU  - Matilda Katan
AU  - Jamie Bilsland
AU  - Paramita Chakrabaty
AU  - Todd E Golde
AU  - Paul J Whiting
TI  - Alzheimer’s disease Phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
AID  - 10.1101/409706
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 409706
4099  - http://biorxiv.org/content/early/2018/09/08/409706.short
4100  - http://biorxiv.org/content/early/2018/09/08/409706.full
AB  - Recent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset AD (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.We confirmed that PLCG2 expression is restricted primarily to microglia in both the healthy and AD brain. Functional analysis of the P522R variant in heterologous systems demonstrated a small hypermorphic effect of the mutation on enzyme function. 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.SUMMARY The PLCG2 P522R variant is protective against Alzheimer’s disease (AD). We show that PLCG2 is expressed in CNS-resident myeloid cells, and the P522R polymorphism weakly activates enzyme function. These data suggest that activation of PLCG2 and not inhibition could be therapeutically beneficial in AD.