Neuronal downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease hallmarks
Coulon, A.; Rabiller, F.; Takalo, M.; Roy, A.; Martiskainen, H.; Siedlecki-Wullich, D.; Mendes, T.; Lemeu, C.; Carvalho, L.-I.; Ehrardt, A.; Melo de Ferias, A. R.; Hulsman, M.; Najdek, C.; Lannette-Weimann, N.; Freire-Regatillo, A.; Amouyel, P.; Charbonnier, C.; Dols-Icardo, O.; Jeskanen, H.; Kuulasmaa, T.; Kurki, M.; Hardy, J.; Wagner, M.; Heikkinen, S.; Holstege, H.; Makinen, P.; Nicolas, G.; Mead, S.; Wagner, M.; Ramirez, A.; Rauramaa, T.; Palotie, A.; Sims, R.; Soininen, H.; van Swieten, J.; Williams, J.; Willman, R.-M.; Bellenguez, C.; Grenier-Boley, B.; Gelle, C.; Lambert, E.; Ayral, A.-
Show abstract
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 A{beta} and Tau phosphorylation, potentially via the AKT/GSK3{beta} 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/PLC{gamma}2 levels, consistent with nonsense-mediated mRNA decay mechanisms. Restoring PLC{gamma}2 levels in shPLCG2-hNCs fully reversed the disease-related phenotypes. Our findings indicate that the downregulation of PLC{gamma}2 increases the risk of AD by impairing synaptic function and increasing the levels of A{beta} and Tau phosphorylation in neurons.
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