PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures

We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and by increasing Aβ levels and Tau phosphorylation in neurons.

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Journal
Nature Genetics
Published
2026-08-14
DOI
https://doi.org/10.1038/s41588-026-02709-5
Primary Topic
Microtubule and mitosis dynamics
Type
article
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0.00

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article

PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures

Julia TCW, Anne‐Marie Ayral, Camille Charbonnier, Florie Demiautte et al.
Nature Genetics
Microtubule and mitosis dynamics
article

PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures

Julia TCW, Anne‐Marie Ayral, Camille Charbonnier, Florie Demiautte, Morgane Lemaire, Marc Hulsman, Jean‐Charles Lambert, Nad’a Majerníková, Alejandra Freire‐Regatillo, Audrey Coulon, Heli Jeskanen, Henna Martiskainen, Alfredo Ramı́rez, Julie Dumont, Philippe Amouyel, Manon Muntaner, Rebecca Sims, Dolores Siedlecki‐Wullich, Michael Wagner, Erwan Lambert, Joel T. Haas, Henne Holstege, Jean‐François Deleuze, Julie Williams, Séverine Deforges, Orthis Saha, Delphine Eberlé, Enrico Glaab, Teemu Kuulasmaa, Roosa-Maria Willman, Céline Bellenguez, Julien Chapuis, Sami Heikkinen, Christophe Mulle, Hilkka Soininen, Devrim Kilinc, Tiago Mendes, Mikko Hiltunen, Oriol Dols‐Icardo, Gaël Nicolas, Aarno V. Palotie, Simon Mead, Chloé Najdek, Carla Gelle, Arthur Grenon, Floriane Limoge, Nina lannette-Weimann, Célia Lemeu, Anaël Erhardt, Karine Guyot, Pauline Walle, lukas-iohan carvalho, Mitja Kurki, Benjamin Grenier‐Boley, Petra Mäkinen, Marcos R Costa, John Hardy, Tuomas Rauramaa, Alexandre Pelletier, Avishek Roy, John van Swieten, Florian Rabiller, Mari Takalo, Anne Pernodet, Vance Gao, Ana Raquel Melo de Farias
article en

Abstract

We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and by increasing Aβ levels and Tau phosphorylation in neurons.

Nature Genetics
Boston University (US), Roche (Switzerland) (CH), Universitat Autònoma de Barcelona (ES), Centre National de la Recherche Scientifique (FR), University of Helsinki (FI), Université de Bordeaux (FR), Inserm (FR), University of Eastern Finland (FI), University of Cologne (DE), University of Luxembourg (LU), Université de Lille (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), University Hospital Bonn (DE), Institut Pasteur de Lille (FR), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Hospital de Sant Pau (ES), Centre Hospitalier Universitaire de Lille (FR), Universidade Federal do Rio Grande do Norte (BR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Kuopio University Hospital (FI), Normandie Université (FR), Finland University (FI), Amsterdam Neuroscience (NL), Institute for Neurodegenerative Disorders (US), UK Dementia Research Institute (GB), Institut Interdisciplinaire de Neuroscience (FR), Institute for Molecular Medicine Finland (FI), MRC Prion Unit (GB), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Amsterdam University Medical Centers (NL), University Hospital Cologne (DE), Centre Hospitalier Universitaire de Rouen (FR), University College London (GB), Université de Rouen Normandie (FR), Cardiff University (GB), Vrije Universiteit Amsterdam (NL), Medical Research Council (GB), Erasmus University Rotterdam (NL)
Alzheimer's Association, Itä-Suomen Yliopisto, Edward N. and Della L. Thome Memorial Foundation, Health Resources in Action, EU Joint Programme – Neurodegenerative Disease Research, Fondation Vaincre Alzheimer, Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease, European Genomic Institute for Diabetes, European Commission, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fonds National de la Recherche Luxembourg, Fondation pour la Recherche Médicale, Jane ja Aatos Erkon Säätiö, Centre National de la Recherche Scientifique, Université de Bordeaux, Sigrid Juséliuksen Säätiö, FONDATION ALZHEIMER, UK Dementia Research Institute, Fondation pour la Recherche sur Alzheimer, Medical Research Council, European Regional Development Fund
Openalex Percentile: Top 22%
Microtubule and mitosis dynamics
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