Authors

J Blaze, 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
A Navickas, Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
H L Phillips, Departments of Psychiatry and Behavioral Sciences, Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA
S Heissel, The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
A Plaza-Jennings, Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
S Miglani, Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
H Asgharian, Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
M Foo, Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
C D Katanski, Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
C P Watkins, Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
Z T Pennington, 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
B Javidfar, Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
S Espeso-Gil, Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
B Rostandy, The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
H Alwaseem, The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
C G Hahn, Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USAFollow
H Molina, The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
D J Cai, 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
T Pan, Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
W D Yao, Departments of Psychiatry and Behavioral Sciences, Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA
H Goodarzi, Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
F Haghighi, 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; Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA; Research and Development Service, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA
S Akbarian, 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; Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA

Document Type

Article

Publication Date

8-13-2021

Comments

This article is the author's final published version in Nature Communications, Volume 12, Issue 1, August 2021, Article number 4913

The published version is available at https://doi.org/10.1038/s41467-021-24969-x

Copyright © The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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 m5C levels, resulting in deficits in expression of 70% of tRNAGly 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.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

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Language

English

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Neurosciences Commons

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