PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522.
Document Type
Article
Publication Date
7-13-2021
Publication Title
The EMBO journal
Keywords
JMG
JAX Source
EMBO J 2021 Jul 13; e105603
First Page
105603
Last Page
105603
ISSN
1460-2075
PMID
34254352
DOI
https://doi.org/10.15252/embj.2020105603
Abstract
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
Recommended Citation
Maguire E,
Menzies G,
Phillips T,
Sasner M,
Williams H,
Czubala M,
Evans N,
Cope E,
Sims R,
Howell G,
Lloyd-Evans E,
Williams J,
Allen N,
Taylor P.
PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522. EMBO J 2021 Jul 13; e105603