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

J. Blaze, A. Navickas, H. L. Phillips, S. Heissel, A. Plaza-Jennings, S. Miglani, H. Asgharian, M. Foo, C. D. Katanski, C. P. Watkins, Z. T. Pennington, B. Javidfar, S. Espeso-Gil, B. Rostandy, H. Alwaseem, C. G. Hahn, H. Molina, D. J. Cai, T. Pan, W. D. Yao, H. Goodarzi, F. Haghighi and S. Akbarian ()
Additional contact information
J. Blaze: Icahn School of Medicine at Mt. Sinai
A. Navickas: University of California San Francisco
H. L. Phillips: Upstate Medical University
S. Heissel: The Rockefeller University
A. Plaza-Jennings: Icahn School of Medicine at Mt. Sinai
S. Miglani: University of California San Francisco
H. Asgharian: University of California San Francisco
M. Foo: University of Chicago
C. D. Katanski: University of Chicago
C. P. Watkins: University of Chicago
Z. T. Pennington: Icahn School of Medicine at Mt. Sinai
B. Javidfar: Icahn School of Medicine at Mt. Sinai
S. Espeso-Gil: Icahn School of Medicine at Mt. Sinai
B. Rostandy: The Rockefeller University
H. Alwaseem: The Rockefeller University
C. G. Hahn: Thomas Jefferson University
H. Molina: The Rockefeller University
D. J. Cai: Icahn School of Medicine at Mt. Sinai
T. Pan: University of Chicago
W. D. Yao: Upstate Medical University
H. Goodarzi: University of California San Francisco
F. Haghighi: Icahn School of Medicine at Mt. Sinai
S. Akbarian: Icahn School of Medicine at Mt. Sinai

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24969-x

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