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
Publication Date
8-13-2021
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.
Recommended Citation
Blaze, J; Navickas, A; Phillips, H L; Heissel, S; Plaza-Jennings, A; Miglani, S; Asgharian, H; Foo, M; Katanski, C D; Watkins, C P; Pennington, Z T; Javidfar, B; Espeso-Gil, S; Rostandy, B; Alwaseem, H; Hahn, C G; Molina, H; Cai, D J; Pan, T; Yao, W D; Goodarzi, H; Haghighi, F; and Akbarian, S, "Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior." (2021). Department of Neuroscience Faculty Papers. Paper 56.
https://jdc.jefferson.edu/department_neuroscience/56
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
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Correction to: Nature Communications https://doi.org/10.1038/s41467-021-24969-x, published online 13 August 2021.
The original version of this Article contained an error in the data availability statement, which incorrectly read. ‘The raw and processed mouse RNA sequencing data generated in this study have been deposited in the Gene Expression Omnibus database under accession code GSE165202’. The correct version adds, ‘tRNA, YAMAT, and Ribosome’ after ‘RNA’. This has been corrected in both the PDF and HTML versions of the Article.
The sequencing datasets deposited in GEO associated with this Article were updated shortly after publication to include the tRNA, YAMAT, and Ribosome sequencing data