Altered tRNA expression profile associated with codon-specific proteomic changes in the suicide brain

Suicide is a major public health concern, and the number of deaths by suicide has been increasing in recent years in the US. There are various biological risk factors for suicide, but causal molecular mechanisms remain unknown, suggesting that investigation of novel mechanisms and integrative approaches are necessary. Transfer (t)RNAs and their modifications, including cytosine methylation (m⁵C), have received little attention regarding their role in normal or diseased brain function, though they are dynamic mediators of protein synthesis. tRNA regulation is highly interconnected with proteomic and metabolomic outcomes, suggesting that investigating these multiple levels of molecular regulation together may elucidate more information on neural function and suicide risk. In the current study, we used an integrative ‘omics’ approach to probe tRNA dysregulation, including tRNA expression and tRNA m⁵C, proteomics, and amino acid metabolomics in prefrontal cortex from 98 subjects who died by suicide during an episode of major depressive disorder (MDD) and neurotypical controls. While no changes were detected in amino acid content, results showed increased tRNA^Gly_GCC expression in the suicide brain that is not driven by changes in m⁵C. Proteomics revealed increased expression of proteins with high glycine codon GGC content, demonstrating a strong association between isoacceptor-specific tRNA expression and proteomic outcomes in the suicide brain, which is in line with previous work linking tRNA^Gly with alterations in glycine-rich proteins in a translational rodent model of depression. Further, we confirmed using a rodent model that tRNA^Gly_GCC overexpression was sufficient to increase the expression of proteins with high glycine codon GGC content that were upregulated in the suicide brain. By characterizing the effects of MDD-suicide in human PFC tissue, we now begin to elucidate a novel molecular signature with downstream consequences for psychiatric outcomes.