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Peer-reviewedCC BY-NC-NDNature Genetics

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

  • Audrey Coulon1
  • Florian Rabiller1
  • Mari Takalo2
  • Avishek Roy3
  • Alexandre Pelletier4
  • Henna Martiskainen2
  • Dolores Siedlecki‐Wullich1
  • Nina lannette-Weimann1
  • Nad’a Majerníková1
  • Arthur Grenon5
  • Vance Gao1
  • Anaël Erhardt3
54 more authors
  • Anne Pernodet1
  • Morgane Lemaire1
  • Floriane Limoge1
  • Pauline Walle1
  • Tiago Mendes1
  • Karine Guyot1
  • Célia Lemeu1
  • Lukas Iohan da Cruz Carvalho1
  • Ana Melo de Farias1
  • Marc Hulsman6,7,8
  • Chloé Najdek1
  • Alejandra Freire‐Regatillo1
  • Orthis Saha1
  • Philippe Amouyel1
  • Camille Charbonnier9
  • Jean‐François Deleuze10
  • Oriol Dols‐Icardo11,12
  • Heli Jeskanen2
  • Roosa-Maria Willman2
  • Teemu Kuulasmaa2
  • Mitja Kurki13
  • John Hardy14
  • Sami Heikkinen2
  • Henne H. Holstege6,7,8
  • Petra M. Mäkinen2
  • Gaël Nicolas15
  • Simon Mead16
  • Michael Wagner17,18
  • Alfredo Ramı́rez19,17,20,21,18
  • Tuomas H. Rauramaa22
  • Aarno V. Palotie11
  • Rebecca Sims23
  • Hilkka S. Soininen24
  • John Cornelis Van Swieten25
  • Julie H. Williams26
  • Céline Bellenguez1
  • Carla Gelle1
  • Erwan Lambert1
  • Marcos R Costa27,28,1
  • Julia TCW29,4
  • Enrico Glaab30
  • Anne‐Marie Ayral1
  • Florie Demiautte1
  • Benjamin Grenier‐Boley1
  • Manon Muntaner1
  • Delphine Eberlé5
  • Séverine Deforges3
  • Joel T. Haas5

60 listed; 66 in total.

30 affiliations
  1. 1Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Lille, France
  2. 2Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
  3. 3Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of Bordeaux, Bordeaux, France
  4. 4Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
  5. 5Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, EGID-U1011, Lille, France
  6. 6Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
  7. 7Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
  8. 8Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
  9. 9Univ. Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Biostatistics and CNRMAJ, Rouen, France
  10. 10Commissariat à L'Énergie Atomique et Aux Énergies Alternatives, Centre National de Recherche en Génomique Humaine, Université Paris-Saclay, Gif-sur-Yvette, France
  11. 11Biomedical Research Networking Center on Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
  12. 12Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
  13. 13Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
  14. 14Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK
  15. 15Univ. Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France
  16. 16Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK
  17. 17Department of Cognitive Disorders and Old Age Psychiatry, Medical Faculty, University Hospital Bonn, Bonn, Germany
  18. 18German Center for Neurodegenerative Diseases, Bonn, Germany
  19. 19Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Disease (CECAD), University of Cologne, Cologne, Germany
  20. 20Department of Psychiatry, Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA
  21. 21Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  22. 22Department of Pathology, Kuopio University Hospital, Kuopio, Finland and Unit of Pathology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
  23. 23Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK
  24. 24Department of Neurology, University of Eastern Finland, Kuopio, Finland
  25. 25Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands
  26. 26UK Dementia Research Institute and Moondance Dementia Research Laboratory, Department of Psychological Medicine, Cardiff University, Cardiff, UK
  27. 27Brain Institute, Federal University of Rio Grande do Norte, Natal, Brazil
  28. 28Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland
  29. 29Bioinformatics Program, Faculty of Computing & Data Sciences, Boston University, Boston, MA, USA
  30. 30Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
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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.

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Cite

BibTeXRIS
BibTeX
@article{coulon2026plcg2,
  title = {{PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures}},
  author = {Audrey Coulon and Florian Rabiller and Mari Takalo and Avishek Roy and Alexandre Pelletier and Henna Martiskainen and Dolores Siedlecki‐Wullich and Nina lannette-Weimann and Nad’a Majerníková and Arthur Grenon and Vance Gao and Anaël Erhardt and Anne Pernodet and Morgane Lemaire and Floriane Limoge and Pauline Walle and Tiago Mendes and Karine Guyot and Célia Lemeu and Lukas Iohan da Cruz Carvalho and Ana Melo de Farias and Marc Hulsman and Chloé Najdek and Alejandra Freire‐Regatillo and Orthis Saha and Philippe Amouyel and Camille Charbonnier and Jean‐François Deleuze and Oriol Dols‐Icardo and Heli Jeskanen and Roosa-Maria Willman and Teemu Kuulasmaa and Mitja Kurki and John Hardy and Sami Heikkinen and Henne H. Holstege and Petra M. Mäkinen and Gaël Nicolas and Simon Mead and Michael Wagner and Alfredo Ramı́rez and Tuomas H. Rauramaa and Aarno V. Palotie and Rebecca Sims and Hilkka S. Soininen and John Cornelis Van Swieten and Julie H. Williams and Céline Bellenguez and Carla Gelle and Erwan Lambert and Marcos R Costa and Julia TCW and Enrico Glaab and Anne‐Marie Ayral and Florie Demiautte and Benjamin Grenier‐Boley and Manon Muntaner and Delphine Eberlé and Séverine Deforges and Joel T. Haas},
  journal = {Nature Genetics},
  year = {2026},
  month = aug,
  doi = {10.1038/s41588-026-02709-5},
  url = {https://hal.science/hal-05776225v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures
AU  - Audrey Coulon
AU  - Florian Rabiller
AU  - Mari Takalo
AU  - Avishek Roy
AU  - Alexandre Pelletier
AU  - Henna Martiskainen
AU  - Dolores Siedlecki‐Wullich
AU  - Nina lannette-Weimann
AU  - Nad’a Majerníková
AU  - Arthur Grenon
AU  - Vance Gao
AU  - Anaël Erhardt
AU  - Anne Pernodet
AU  - Morgane Lemaire
AU  - Floriane Limoge
AU  - Pauline Walle
AU  - Tiago Mendes
AU  - Karine Guyot
AU  - Célia Lemeu
AU  - Lukas Iohan da Cruz Carvalho
AU  - Ana Melo de Farias
AU  - Marc Hulsman
AU  - Chloé Najdek
AU  - Alejandra Freire‐Regatillo
AU  - Orthis Saha
AU  - Philippe Amouyel
AU  - Camille Charbonnier
AU  - Jean‐François Deleuze
AU  - Oriol Dols‐Icardo
AU  - Heli Jeskanen
AU  - Roosa-Maria Willman
AU  - Teemu Kuulasmaa
AU  - Mitja Kurki
AU  - John Hardy
AU  - Sami Heikkinen
AU  - Henne H. Holstege
AU  - Petra M. Mäkinen
AU  - Gaël Nicolas
AU  - Simon Mead
AU  - Michael Wagner
AU  - Alfredo Ramı́rez
AU  - Tuomas H. Rauramaa
AU  - Aarno V. Palotie
AU  - Rebecca Sims
AU  - Hilkka S. Soininen
AU  - John Cornelis Van Swieten
AU  - Julie H. Williams
AU  - Céline Bellenguez
AU  - Carla Gelle
AU  - Erwan Lambert
AU  - Marcos R Costa
AU  - Julia TCW
AU  - Enrico Glaab
AU  - Anne‐Marie Ayral
AU  - Florie Demiautte
AU  - Benjamin Grenier‐Boley
AU  - Manon Muntaner
AU  - Delphine Eberlé
AU  - Séverine Deforges
AU  - Joel T. Haas
PY  - 2026
DA  - 2026/08/14
JO  - Nature Genetics
DO  - 10.1038/s41588-026-02709-5
UR  - https://hal.science/hal-05776225v1
AB  - 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.
SN  - 1061-4036
SN  - 1546-1718
ER  -