| First Author | Maguire E | Year | 2021 |
| Journal | EMBO J | Pages | e105603 |
| PubMed ID | 34254352 | Mgi Jnum | J:308279 |
| Mgi Id | MGI:6728752 | Doi | 10.15252/embj.2020105603 |
| Citation | Maguire E, et al. (2021) PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCgamma2 R522. EMBO J :e105603 |
| abstractText | 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 PLCgamma2 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 Abeta oligomers. Expression of the PLCgamma2-R522 variant resulted in increased stimulus-dependent PIP2 depletion and reduced basal PIP2 levels in vivo. Furthermore, it was associated with impaired phagocytosis and enhanced endocytosis. PLCgamma2 acts downstream of other AD-related factors, such as TREM2 and CSF1R, and alterations in its activity directly impact cell function. The inherent druggability of enzymes such as PLCgamma2 raises the prospect of PLCgamma2 manipulation as a future therapeutic approach in AD. |
