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The hypermorphic PLCγ2 S707Y variant dysregulates microglial cell function – Insight into PLCγ2 activation in brain health and disease, and opportunities for therapeutic modulation

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Bull, Daniel, Matte, Julie C., Navarron, Carmen M., McIntyre, Rebecca, Whiting, Paul, Katan, Matilda, Ducotterd, Fiona, Magno, Lorenza·2024·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
DOI 10.1016/j.bbadis.2023.166978

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Abstract

Abstract Phospholipase C-gamma 2 (PLCγ2) is highly expressed in hematopoietic and immune cells, where it is a key signalling node enabling diverse cellular functions. Within the periphery, gain-of-function (GOF) PLCγ2 variants, such as the strongly hypermorphic S707Y, cause severe immune dysregulation. The milder hypermorphic mutation PLCγ2 P522R increases longevity and confers protection in central nervous system (CNS) neurodegenerative disorders, implicating PLCγ2 as a novel therapeutic target for treating these CNS indications. Currently, nothing is known about what consequences strong PLCγ2 GOF has on CNS functionality, and more precisely on the specific biological functions of microglia. Using the PLCγ2 S707Y variant as a model of chronic activation we investigated the functional consequences of strong PLCγ2 GOF on human microglia. PLCγ2 S707Y expressing human inducible pluripotent stem cells (hiPSC)-derived microglia exhibited hypermorphic enzymatic activity under both basal and stimulated conditions, compared to PLCγ2 wild type. Despite the increase in PLCγ2 enzymatic activity, the PLCγ2 S707Y hiPSC-derived microglia display diminished functionality for key microglial processes including phagocytosis and cytokine secretion upon inflammatory challenge. RNA sequencing revealed a downregulation of genes related to innate immunity and response, providing molecular support for the phenotype observed. Our data suggests that chronic activation of PLCγ2 elicits a detrimental phenotype that is contributing to unfavourable CNS functions, and informs on the therapeutic window for targeting PLCγ2 in the CNS. Drug candidates targeting PLCγ2 will need to precisely mimic the effects of the PLCγ2 P522R variant on microglial function, but not those of the PLCγ2 S707Y variant. Highlights The impact of strongly hypermorphic variants of PLCγ2 have not been studied in brain and yet PLCγ2 is implicated in modifying risk of CNS disorders including Alzheimer’s disease To address this, we explored the role of the strongly hypermorphic PLCγ2 S707Y variant in hiPSC-derived microglia S707Y increases PLCγ2 enzymatic activity and intracellular calcium flux Phagocytosis and cytokine production are diminished in PLCγ2 S707Y microglia PLCγ2 S707Y downregulates expression of genes related to innate immunity and response Modulation of PLCγ2 for therapy must recapitulate the positive effects of moderate hypermorphic variants on microglial functions whilst avoiding detrimental effects of strongly hypermorphic variants like PLCγ2 S707Y Graphical abstract

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  • There are several hypermorphic variants in PLCG2 that have been associated with autoimmune disease and cancer.

    “There are several hypermorphic variants in PLCG2 that have been associated with autoimmune disease and cancer [58–61, 66].”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [66]

    The Introduction (p. 3) says several strongly hypermorphic PLCγ2 variants cause autoimmune phenotypes. It also mentions PLCγ2 variants associated with drug resistance in cancer, but does not say those cancer-associated variants are hypermorphic. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The PLCγ2-P522R variant is a mild hypermorph, which only slightly increases the enzymatic activity of PLCγ2 compared with other hypermorphic variants, such as PLCγ2-S707Y, which is associated with severe autoinflammatory symptoms and immune dysregulation.

    “the PLCγ2-P522R variant is a mild hypermorph, which only slightly increases the enzymatic activity of PLCγ2 compared with other hypermorphic variants, such as PLCγ2-S707Y, which is associated with severe autoinflammatory symptoms and immune dysregulation [66].”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [66]

  • iPSC-derived microglia expressing another highly active APLAID variant display diminished functionality for key microglial processes.

    “This possibility is further strengthened by our recent findings that the iPSC-derived microglia expressing another highly active APLAID variant display diminished functionality for key microglial processes (Bull et al., 2024).”

    From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Bull et al., 2024

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Authors
Bull, D., Matte, J. C., Navarron, C. M., McIntyre, R., Whiting, P., Katan, M., Ducotterd, F., & Magno, L.
Affiliations
  • Alzheimer’s Research UK (GB)
  • Wellcome Sanger Institute (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • Institute of Structural and Molecular Biology (GB)
Corresponding author
  • Ducotterd, Fiona
  • Magno, Lorenza
ORCID
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Publisher
Elsevier BV
Published
2024-02
Volume
1870
Issue
2
Pages
166978
ISSN
0925-4439 (ISSN-L)
DOI
10.1016/j.bbadis.2023.166978
OpenAlex
W4389396280
Cited by
3
References
16
Citations by year
2026: 1 · 2025: 1 · 2024: 1
FWCI
0.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Fidelity Foundation
  • Wellcome Trust
  • GlaxoSmithKline
  • Alzheimer’s Research UK
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
PLCγ2, microglia, gain-of-function mutations, phagocytosis, cytokine production, innate immunity, neurodegenerative diseases, phospholipase C signaling
MeSH terms
Brain, Humans, Immunity, Innate, Phagocytosis, Microglia, Neurodegenerative Diseases, Phospholipase C gamma

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