| Title: |
Neuronal downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease hallmarks |
| Authors: |
Coulon, Audrey; Rabiller, Florian; Takalo, Mari; Roy, Avishek; Martiskainen, Henna; Siedlecki-Wullich, Dolores; Mendes, Tiago; Lemeu, Celia; Carvalho, Lukas-Iohan; Ehrardt, Anaël; Melo de Farias, Ana Raquel; Hulsman, Marc; Najdek, Chloé; Lannette-Weimann, Nina; Freire-Regatillo, Alejandra; Amouyel, Philippe; Charbonnier, Camille; Dols-Icardo, Orio; Jeskanen, Heli; Willman, Roosa-Maria; Kuulasmaa, Teemu; Kurki, Mitja; Hardy, John; Wagner, Richard; Heikkinen, Sami; Holstege, Henne; Mäkinen, Petra; Nicolas, Gaël; Mead, Simon; Wagner, Michael; Ramirez, Alfredo; Rauramaa, Tuomas; Palotie, Aarno; Sims, Rebecca; Soininen, Hilkka; van Swieten, John; Williams, Julie; Bellenguez, Céline; Grenier-Boley, Benjamin; Gelle, Carla; Lambert, Erwan; Ayral, Anne-Marie; Demiautte, Florie; Costa, Marcos; Deforges, Séverine; Kilinc, Devrim; Mulle, Christophe; Chapuis, Julien; Hiltunen, Mikko; Dumont, Julie; Lambert, Jean-Charles |
| Contributors: |
Interdisciplinary Institute for Neuroscience / Institut interdisciplinaire de neurosciences Bordeaux (IINS); Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS); Institut National de la Santé et de la Recherche Médicale (INSERM); Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)); Institut National de la Transfusion Sanguine Paris (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre / Abymes Guadeloupe -Université des Antilles (UA)-Université Paris Cité (UPCité); Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex); Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité) |
| Source: |
https://hal.science/hal-05544909 ; 2026. |
| Publisher Information: |
CCSD |
| Publication Year: |
2026 |
| Subject Terms: |
[SDV]Life Sciences [q-bio] |
| Description: |
We developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may impair synaptic mechanisms in rat primary neuronal cultures. Out of the gene targets identified, we found that shRNA-mediated downregulation of Plcg2 in mouse dentate gyrus neurons consistently impaired dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and was associated with increased levels of Aβ and Tau phosphorylation, potentially via the AKT/GSK3β axis. Very rare PLCG2 loss-of-function (LoF) variants were associated with a 10-fold increased AD risk. PLCG2 LoF carriers exhibit low mRNA/protein PLCG2/ PLCγ2 levels, consistent with nonsense-mediated mRNA decay mechanisms. Restoring PLCγ2 levels in shPLCG2-hNCs fully reversed the disease-related phenotypes. Our findings indicate that the downregulation of PLCγ2 increases the risk of AD by impairing synaptic function and increasing the levels of Aβ and Tau phosphorylation in neurons. |
| Document Type: |
report |
| Language: |
English |
| Relation: |
BIORXIV: 2024.04.29.591575 |
| DOI: |
10.1101/2024.04.29.591575 |
| Availability: |
https://hal.science/hal-05544909; https://doi.org/10.1101/2024.04.29.591575 |
| Accession Number: |
edsbas.9336D043 |
| Database: |
BASE |