PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522

Maguire, Emily, Menzies, Georgina E. ORCID: https://orcid.org/0000-0002-6600-6507, Phillips, Thomas, Sasner, Michael, Williams, Harriet M. ORCID: https://orcid.org/0000-0001-7571-1868, Czubala, Magdalena A. ORCID: https://orcid.org/0000-0001-9881-1095, Evans, Neil ORCID: https://orcid.org/0000-0002-5458-6065, Cope, Emma L., Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, Howell, Gareth R., Lloyd-Evans, Emyr ORCID: https://orcid.org/0000-0002-3626-1611, Williams, Julie ORCID: https://orcid.org/0000-0001-7571-1868, Allen, Nicholas D. ORCID: https://orcid.org/0000-0003-4009-186X and Taylor, Philip R ORCID: https://orcid.org/0000-0003-0163-1421 2021. PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522. EMBO Journal 40 (17) , e105603. 10.15252/embj.2020105603

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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 PIP2 depletion and reduced basal PIP2 levels in vivo. Furthermore, it was associated with impaired phagocytosis and enhanced endocytosis. PLCγ2 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 PLCγ2 raises the prospect of PLCγ2 manipulation as a future therapeutic approach in AD.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Biosciences MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	EMBO Press
ISSN:	0261-4189
Funders:	Wellcome Trust
Date of First Compliant Deposit:	15 July 2021
Date of Acceptance:	4 June 2021
Last Modified:	05 Dec 2023 02:58
URI:	https://orca.cardiff.ac.uk/id/eprint/142537

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