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Altered tRNA expression profile associated with codon-specific proteomic changes in the suicide brain
J Blaze1, S Chen2,3, S Heissel4
1Department of Psychiatry, Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jenniferblaze@gmail.com.
Abstract:
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 tRNAGlyGCC 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 tRNAGly with alterations in glycine-rich proteins in a translational rodent model of depression. Further, we confirmed using a rodent model that tRNAGlyGCC 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.
Insights
Suicide is a growing public health issue. This study found increased transfer RNA (tRNA) Glycine GCC expression in the brains of individuals with major depressive disorder (MDD) who died by suicide, impacting protein expression.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Suicide represents a significant public health challenge with increasing mortality rates.
- The precise molecular mechanisms underlying suicide risk remain largely unknown, necessitating novel investigative approaches.
- Transfer RNAs (tRNAs) and their modifications are critical for protein synthesis but their role in brain function and suicide is understudied.
Purpose of the Study:
- To investigate tRNA dysregulation and its downstream effects in the prefrontal cortex of individuals who died by suicide.
- To explore the relationship between tRNA expression, m5C modification, proteomics, and amino acid metabolomics in suicide.
- To identify novel molecular signatures associated with major depressive disorder (MDD) and suicide.
Main Methods:
- An integrative 'omics' approach was employed, analyzing tRNA expression, tRNA m5C, proteomics, and amino acid metabolomics.
- Samples were obtained from the prefrontal cortex of 98 individuals with MDD who died by suicide and neurotypical controls.
- A rodent model was used to validate findings related to tRNA overexpression and protein expression.
Main Results:
- No significant changes in amino acid content were observed between groups.
- Increased expression of tRNA Glycine GCC (tRNA^Gly_GCC) was detected in the suicide brain, independent of m5C modification.
- Proteomics revealed elevated expression of proteins rich in glycine codons (GGC), correlating with tRNA^Gly_GCC levels.
Conclusions:
- Specific tRNA dysregulation, particularly tRNA^Gly_GCC, is linked to altered protein expression in the suicide brain.
- These findings highlight a novel molecular pathway potentially contributing to psychiatric outcomes in MDD and suicide.
- The study establishes a connection between tRNA expression and glycine-rich protein alterations, supported by a rodent model.
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