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

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.

The Effect of Methyltransferase NSUN2 in Stroke

“…The brain's translational machinery bears promise for psychiatric disease treatment(Aguilar-Valles et al,2021;Fine et al,2019).NSUN2 is a vital epitranscriptome regulator in mature neurons, and its expression and activity in mature neurons is critical for complex behaviors including synaptic transmission and emotional memory. De ciency of neuronal NSUN2 can cause impaired neurotransmitter transduction and synaptic signaling causing emotional behavioral variations(Blaze et al,2021).NSUN2 expression is signi cantly reduced in equine tissues of Alzheimer's patients, thereby decreasing tRNA methylation and promoting the development of Alzheimer's disease(Wu et al,2021). As revealed from the results here, NSUN2 knockdown signi cantly up-regulated neurobehavioral scores, brain infarct size and neuronal death, while decreasing survival in a mouse MCAO/R model.…”

The tRNA thiolation-mediated translational control is essential for plant immunity

“…The role of mcm 5 s 2 U modification in translation was reported in several studies (Johansson et al, 2008; Klassen et al, 2020; Koplin et al, 2010; Laxman et al, 2013; Nedialkova and Leidel, 2015; Rezgui et al, 2013; Tavares et al, 2021). In addition to the mcm 5 s 2 U modification, tRNA contains many other types of modifications such as the m 5 C modification (Blaze et al, 2021). To test whether the m 5 C modification has similar functions in regulating the expression of long proteins, we analyzed the proteome data of the m 5 C mutant.…”

“…In addition to the mcm 5 s 2 U modification, tRNA contains many other types of modifications such as the m 5 C modification (Blaze et al, 2021). To test…”

RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis

“…NSUN2 deficiency resulted in changes in 1488 proteins in the prefrontal cortex, together with a decline in translation efficiency associated with a glycine-codon defect. Consequently, the mice displayed impaired synaptic signaling of pyramidal neurons in the prefrontal cortex and defective contextual fear memory [166]. Disruption of NSUN2-mediated tRNA methylation causes 5 regions of tRNA fragments to accumulate, impairing the generation of upper layer neurons and brain development in mice [167].…”