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DNA 修复蛋白 DNA-PKcs 通过 PSD-95 磷酸化和稳定性调节突触可塑性。

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

机构信息

Istituto Superiore di Sanita', Department of Neuroscience, 00161, Rome, Italy.

Institute of Translational Pharmacology, National Research Council, 00133, Rome, Italy.

出版信息

EMBO Rep. 2024 Aug;25(8):3707-3737. doi: 10.1038/s44319-024-00198-3. Epub 2024 Jul 31.

DOI:10.1038/s44319-024-00198-3
PMID:39085642
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11315936/
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.

摘要

关键的 DNA 修复酶 DNA-PKcs 具有多种重要的细胞功能。在小鼠中丧失 DNA-PKcs 的活性已经揭示了其在免疫系统和神经系统中的重要作用。在人类中，DNA-PKcs 是大脑发育和功能的关键因素，因为 prkdc 基因突变会导致严重的神经缺陷，如小头畸形和癫痫发作，这预示着 DNA-PKcs 在神经元中具有未知的作用。在这里，我们表明 DNA-PKcs 调节突触可塑性。我们证明 DNA-PKcs 定位于突触，并磷酸化 PSD-95 上新鉴定的控制 PSD-95 蛋白稳定性的残基。DNA-PKcs -/- 小鼠的特征是长时程增强作用（LTP）受损、神经元形态改变以及突触后蛋白水平降低。当在 DNA-PKcs -/- 小鼠中过表达时，一种组成性磷酸化的 PSD-95 突变体能挽救 LTP 损伤。我们的研究确定了 DNA-PKcs 在调节神经元可塑性方面的一个新的生理功能，超越了基因组稳定性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e7d/11315936/200bae79584d/44319_2024_198_Fig13_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e7d/11315936/2c226e3ea7e7/44319_2024_198_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e7d/11315936/3d7582529d98/44319_2024_198_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e7d/11315936/330b78a19400/44319_2024_198_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e7d/11315936/83617dd83b9b/44319_2024_198_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e7d/11315936/f30cf28eae4a/44319_2024_198_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e7d/11315936/40ae1e9a2aed/44319_2024_198_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e7d/11315936/200bae79584d/44319_2024_198_Fig13_ESM.jpg

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