Nature genetics · 2026

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

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Coulon Audrey, Rabiller Florian, Takalo Mari, Roy Avishek, Pelletier Alexandre, Martiskainen Henna, Siedlecki-Wullich Dolores, Lannette-Weimann Nina, Majerníková Naďa, Grenon Arthur, Gao Vance, Erhardt Anaël, Pernodet Anne, Lemaire Morgane, Limoge Floriane, Walle Pauline, Mendes Tiago, Guyot Karine, Lemeu Célia, Carvalho Lukas-Iohan, Melo de Farias Ana Raquel, Hulsman Marc, Najdek Chloé, Freire-Regatillo Alejandra, Saha Orthis, Amouyel Philippe, Charbonnier Camille, Deleuze Jean-François, Dols-Icardo Orio, Jeskanen Heli, Willman Roosa-Maria, Kuulasmaa Teemu, Kurki Mitja, Hardy John, 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, Gelle Carla, Lambert Erwan, Costa Marcos R, Tcw Julia, Glaab Enrico, Ayral Anne-Marie, Demiautte Florie, Grenier-Boley Benjamin, Muntaner Manon, Eberlé Delphine, Deforges Séverine, Haas Joel T, Kilinc Devrim, Mulle Christophe, Chapuis Julien, Hiltunen Mikko, Dumont Julie, Lambert Jean-Charles

Аннотация

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.

Предметные рубрики MeSH

Alzheimer Disease Animals Phospholipase C gamma Humans Neurons Down-Regulation Synapses Mice tau Proteins Phosphorylation Cells, Cultured Rats Amyloid beta-Peptides Dentate Gyrus

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

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Аннотация

Предметные рубрики MeSH