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Publications

Journal Article Ahead of print 1 citation

PubMed: 42601455 DOI: 10.1038/s41588-026-02709-5

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

Nat Genet

Authors: Audrey Coulon, Florian Rabiller, Mari Takalo, Avishek Roy, Alexandre Pelletier, Henna Martiskainen, Dolores Siedlecki-Wullich, Nina Lannette-Weimann, Naďa Majerníková, Arthur Grenon, Vance Gao, Anaël Erhardt, Anne Pernodet, Morgane Lemaire, Floriane Limoge, Pauline Walle, Tiago Mendes, Karine Guyot, Célia Lemeu, Lukas-Iohan Carvalho, Ana Raquel Melo de Farias, Marc Hulsman, Chloé Najdek, Alejandra Freire-Regatillo, Orthis Saha, Philippe Amouyel, Camille Charbonnier, Jean-François Deleuze, Orio Dols-Icardo, Heli Jeskanen, Roosa-Maria Willman, Teemu Kuulasmaa, Mitja Kurki, John Hardy, Sami Heikkinen, Henne Holstege, Petra Mäkinen, Gaël Nicolas, Simon Mead, Michael Wagner, Alfredo Ramirez, Tuomas Rauramaa, Aarno Palotie, Rebecca Sims, Hilkka Soininen, John van Swieten, Julie Williams, Céline Bellenguez, Carla Gelle, Erwan Lambert … and 16 other authors

Affiliations

  • Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Lille, France.
  • Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
  • Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of Bordeaux, Bordeaux, France.
  • Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
  • Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, EGID-U1011, Lille, France.
  • Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
  • Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
  • Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
  • Univ. Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Biostatistics and CNRMAJ, Rouen, France.
  • Commissariat à L'Énergie Atomique et Aux Énergies Alternatives, Centre National de Recherche en Génomique Humaine, Université Paris-Saclay, Gif-sur-Yvette, France.
  • Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
  • Biomedical Research Networking Center on Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
  • Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
  • Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK.
  • Univ. Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France.
  • Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.
  • Department of Cognitive Disorders and Old Age Psychiatry, Medical Faculty, University Hospital Bonn, Bonn, Germany.
  • German Center for Neurodegenerative Diseases, Bonn, Germany.
  • Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Department of Psychiatry, Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
  • Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Disease (CECAD), University of Cologne, Cologne, Germany.
  • Department of Pathology, Kuopio University Hospital, Kuopio, Finland and Unit of Pathology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
  • Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
  • Department of Neurology, University of Eastern Finland, Kuopio, Finland.
  • Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands.
  • UK Dementia Research Institute and Moondance Dementia Research Laboratory, Department of Psychological Medicine, Cardiff University, Cardiff, UK.

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.

MeSH

Neurons, Alzheimer Disease, Down-Regulation, Genetics, Medical