Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior
Jennifer Blaze, Albertas Navickas, Hannah Phillips, Søren Heissel, Amara Plaza-Jennings, Sohit Miglani, Hosseinali Asgharian, M. Foo, Christopher D. Katanski, Christopher Watkins, Zachary T. Pennington, Behnam Javidfar, Sergio Espeso‐Gil, Bety Rostandy, Hanan Alwaseem, C-G Hahn, Henrik Molina, Denise J. Cai, Tao Pan, Wei‐Dong Yao, Hani Goodarzi, Fatemeh Haghighi, Schahram Akbarian
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 m 5 C levels, resulting in deficits in expression of 70% of tRNA Gly 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.