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

Autor: Behnam Javidfar, Wei-Dong Yao, Fatemeh Haghighi, M. Foo, C. P. Watkins, C. G. Hahn, Søren Heissel, H. L. Phillips, Schahram Akbarian, Sohit Miglani, Jennifer Blaze, Henrik Molina, B. Rostandy, Zachary T. Pennington, Albertas Navickas, Tao Pan, Hani Goodarzi, Denise J. Cai, Hanan Alwaseem, A. Plaza-Jennings, Sergio Espeso-Gil, Christopher D. Katanski, Hosseinali Asgharian
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Proteomics
Proteome
General Physics and Astronomy
Inbred C57BL
Synaptic Transmission
Transgenic
Epigenesis
Genetic
Mice
RNA
Transfer
Epigenetics and behaviour
Prefrontal cortex
skin and connective tissue diseases
Glycine receptor
Mice
Knockout
Neurons
Multidisciplinary
Chemistry
Depression
Epigenetics and plasticity
Cell biology
Mental Health
Transfer RNA
DNA methylation
Neurological
Synaptic signaling
Signal Transduction
Knockout
Science
Prefrontal Cortex
Mice
Transgenic
Neurotransmission
Molecular neuroscience
Basic Behavioral and Social Science
General Biochemistry
Genetics and Molecular Biology
Article
Glutamatergic
Genetic
Behavioral and Social Science
Animals
Author Correction
Depressive Disorder
Gene Expression Profiling
Neurosciences
General Chemistry
Methyltransferases
Brain Disorders
Mice
Inbred C57BL
Transfer
Synaptic plasticity
RNA
sense organs
Epigenesis
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021)
Nature communications, vol 12, iss 1
Nature Communications
ISSN: 2041-1723
Popis: 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.
The link between tRNA modifications, protein translation, and behavior is unclear. Here, the authors show that neuronal Nsun2 deficiency results in codon-specific epitranscriptomic changes of Gly-tRNAs and proteomic changes affecting synaptic signaling and behavior in mice.
Databáze: OpenAIRE
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