The DNA repair protein DNA-PKcs modulates synaptic plasticity via PSD-95 phosphorylation and stability.

Autor:	Mollinari C; Istituto Superiore di Sanita', Department of Neuroscience, 00161, Rome, Italy.; Institute of Translational Pharmacology, National Research Council, 00133, Rome, Italy., Cardinale A; Holostem Srl, 41125, Modena, Italy., Lupacchini L; IRCCS San Raffaele Roma, 00163, Rome, Italy., Martire A; Istituto Superiore di Sanita', National Centre for Drug Research and Evaluation, 00161, Rome, Italy., Chiodi V; Istituto Superiore di Sanita', National Centre for Drug Research and Evaluation, 00161, Rome, Italy., Martinelli A; Istituto Superiore di Sanita', Experimental Animal Welfare Sector, 00161, Rome, Italy., Rinaldi AM; Department of Systems Medicine, 'Tor Vergata' University of Rome, 00133, Rome, Italy., Fini M; IRCCS San Raffaele Roma, 00163, Rome, Italy., Pazzaglia S; ENEA SSPT-TECS-TEB, Casaccia Research Center, Division of Health Protection Technology (TECS), Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123, Rome, Italy., Domenici MR; Istituto Superiore di Sanita', National Centre for Drug Research and Evaluation, 00161, Rome, Italy., Garaci E; IRCCS San Raffaele Roma, 00163, Rome, Italy.; MEBIC Consortium, 00166, Rome, Italy., Merlo D; Istituto Superiore di Sanita', Department of Neuroscience, 00161, Rome, Italy. daniela.merlo@iss.it.
Jazyk:	angličtina
Zdroj:	EMBO reports [EMBO Rep] 2024 Aug; Vol. 25 (8), pp. 3707-3737. Date of Electronic Publication: 2024 Jul 31.
DOI:	10.1038/s44319-024-00198-3
Abstrakt:	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).)
Databáze:	MEDLINE
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