PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522.
The EMBO journal
EMBO J 2021 Jul 13; e105603
Variants identified in genome-wide association studies have implicated immune pathways in the development of Alzheimer's disease (AD). Here, we investigated the mechanistic basis for protection from AD associated with PLCγ2 R522, a rare coding variant of the PLCG2 gene. We studied the variant's role in macrophages and microglia of newly generated PLCG2-R522-expressing human induced pluripotent cell lines (hiPSC) and knockin mice, which exhibit normal endogenous PLCG2 expression. In all models, cells expressing the R522 mutation show a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This manifests as enhanced release of cellular calcium ion stores in response to physiologically relevant stimuli like Fc-receptor ligation or exposure to Aβ oligomers. Expression of the PLCγ2-R522 variant resulted in increased stimulus-dependent PIP
Maguire, Emily; Menzies, Georgina E; Phillips, Thomas; Sasner, Michael; Williams, Harriet M; Czubala, Magdalena A; Evans, Neil; Cope, Emma L; Sims, Rebecca; Howell, Gareth R; Lloyd-Evans, Emyr; Williams, Julie; Allen, Nicholas D; and Taylor, Philip R, "PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522." (2021). Faculty Research 2021. 155.