Apr 28, 2020

The Alzheimer's disease protective P522R variant of PLCG2, consistently enhances stimulus-dependent PLCγ2 activation, depleting substrate and altering cell function.

BioRxiv : the Preprint Server for Biology
E. MaguirePhilip R Taylor

Abstract

Recent genome-wide association studies of Alzheimer's disease (AD) have identified variants implicating immune pathways in disease development. A rare coding variant of PLCG2, which encodes PLC{gamma}2, shows a significant protective effect for AD (rs72824905, P522R, P=5.38x10-10, Odds Ratio = 0.68). Molecular dynamic modelling of the PLC{gamma}2-R522 variant, situated within the auto-inhibitory domain of PLC{gamma}2, suggests a structural change to the protein. Through CRISPR-engineering we have generated novel PLCG2-R522 harbouring human induced pluripotent cell lines (hiPSC) and a mouse knockin model, neither of which exhibits alterations in endogenous PLCG2 expression. Mouse microglia and macrophages and hiPSC-derived microglia-like cells with the R522 mutation, all demonstrate a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This signalling alteration manifests as enhanced cellular Ca2+ store release (~20-40% increase) in response to physiologically-relevant stimuli (e.g. Fc receptor ligation and A{beta} oligomers). This hyperfunctionality resulted in increased PIP2 depletion in the cells with the PLC{gamma}2-R522 variant after exposure to stimuli and reduced basal de...Continue Reading

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Mentioned in this Paper

Study
Microarray Analysis
Meta-Analysis (Publications)
Meta Analysis (Statistical Procedure)
Genes
Definition
Equus asinus
Cross Validation
Gene Expression
Evaluation

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