1. The DNA repair protein DNA-PKcs modulates synaptic plasticity via PSD-95 phosphorylation and stability.
- Author
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Mollinari C, Cardinale A, Lupacchini L, Martire A, Chiodi V, Martinelli A, Rinaldi AM, Fini M, Pazzaglia S, Domenici MR, Garaci E, and Merlo D
- Subjects
- Animals, Phosphorylation, Mice, Neurons metabolism, Mice, Knockout, Humans, Synapses metabolism, DNA Repair, Nuclear Proteins metabolism, Nuclear Proteins genetics, DNA-Binding Proteins, DNA-Activated Protein Kinase metabolism, DNA-Activated Protein Kinase genetics, Disks Large Homolog 4 Protein metabolism, Disks Large Homolog 4 Protein genetics, Neuronal Plasticity, Long-Term Potentiation, Protein Stability
- Abstract
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., (© 2024. The Author(s).)
- Published
- 2024
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