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

J Blaze¹, S Chen^2,3, 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.

Molecular Psychiatry

|January 14, 2025

Summary

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.

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Published on: April 13, 2022

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.