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神经元 Nsun2 缺乏导致 tRNA 表转录组改变和蛋白质组转移，影响突触信号传递和行为。

Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior.

机构信息

Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.

Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.

出版信息

Nat Commun. 2021 Aug 13;12(1):4913. doi: 10.1038/s41467-021-24969-x.

DOI:10.1038/s41467-021-24969-x
PMID:34389722
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8363735/
Abstract

Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA mC levels, resulting in deficits in expression of 70% of tRNA isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.

摘要

tRNA 功能与大脑蛋白质组学到认知和复杂行为的关联中的表观转录机制尚未得到很好的描述。在这里，我们报告了神经元 tRNA 胞嘧啶甲基化遗传破坏后与抑郁相关的行为的双向变化，包括条件性消融和 Nsun2 的转基因过表达在小鼠前额叶皮层（PFC）中。神经元 Nsun2 缺陷与 tRNA mC 水平降低有关，导致 70%的 tRNA 同功密码子表达缺陷。总的来说，神经元 Nsun2 缺陷后有 1488/5820 种蛋白质发生变化，同时存在翻译效率的甘氨酸密码子特异性缺陷。对谷氨酸能神经传递至关重要的 Gly-rich 蛋白的丧失与 PFC 锥体神经元的突触信号转导受损和情境性恐惧记忆缺陷有关。神经元转译组的变化也与甘氨酸生物合成增加 146%有关。这些发现强调了成年 PFC 中甘氨酰 tRNA 的甲基化敏感性。此外，它们将突触可塑性和复杂行为与对应 tRNA 的表观转录修饰以及与特定氨基酸相关的蛋白质组平衡联系起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/a69b7bdf4e66/41467_2021_24969_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/db6d9de7f2cd/41467_2021_24969_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/0cc3ff0a3fd6/41467_2021_24969_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/20157225c1b7/41467_2021_24969_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/3b03f3be1986/41467_2021_24969_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/a69b7bdf4e66/41467_2021_24969_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/db6d9de7f2cd/41467_2021_24969_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/0cc3ff0a3fd6/41467_2021_24969_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/20157225c1b7/41467_2021_24969_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/3b03f3be1986/41467_2021_24969_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/8363735/a69b7bdf4e66/41467_2021_24969_Fig5_HTML.jpg

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