EMBO reports · 2024
The DNA repair protein DNA-PKcs modulates synaptic plasticity via PSD-95 phosphorylation and stability.
СтатьяНазвание и аннотация: Перевод в очереди
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Mollinari Cristiana, Cardinale Alessio, Lupacchini Leonardo, Martire Alberto, Chiodi Valentina, Martinelli Andrea, Rinaldi Anna Maria, Fini Massimo, Pazzaglia Simonetta, Domenici Maria Rosaria, Garaci Enrico, Merlo Daniela
Аннотация
The key DNA repair enzyme DNA-PKcs has several and important cellular functions. Loss of DNA-PKcs activity in mice has revealed essential roles in immune and nervous systems. In humans, DNA-PKcs is a critical factor for brain development and function since mutation of the prkdc gene causes severe neurological deficits such as microcephaly and seizures, predicting yet unknown roles of DNA-PKcs in neurons. Here we show that DNA-PKcs modulates synaptic plasticity. We demonstrate that DNA-PKcs localizes at synapses and phosphorylates PSD-95 at newly identified residues controlling PSD-95 protein stability. DNA-PKcs -/- mice are characterized by impaired Long-Term Potentiation (LTP), changes in neuronal morphology, and reduced levels of postsynaptic proteins. A PSD-95 mutant that is constitutively phosphorylated rescues LTP impairment when over-expressed in DNA-PKcs -/- mice. Our study identifies an emergent physiological function of DNA-PKcs in regulating neuronal plasticity, beyond genome stability.