The TRNA Regulome in Neurodevelopmental and Neuropsychiatric Disease

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2022 May 3

PMID 35505091

Authors

Jennifer Blaze

Schahram Akbarian

Affiliations

Soon will be listed here.

Abstract

Transfer (t)RNAs are 70-90 nucleotide small RNAs highly regulated by 43 different types of epitranscriptomic modifications and requiring aminoacylation ('charging') for mRNA decoding and protein synthesis. Smaller cleavage products of mature tRNAs, or tRNA fragments, have been linked to a broad variety of noncanonical functions, including translational inhibition and modulation of the immune response. Traditionally, knowledge about tRNA regulation in brain is derived from phenotypic exploration of monogenic neurodevelopmental and neurodegenerative diseases associated with rare mutations in tRNA modification genes. More recent studies point to the previously unrecognized potential of the tRNA regulome to affect memory, synaptic plasticity, and affective states. For example, in mature cortical neurons, cytosine methylation sensitivity of the glycine tRNA family (tRNA) is coupled to glycine biosynthesis and codon-specific alterations in ribosomal translation together with robust changes in cognition and depression-related behaviors. In this Review, we will discuss the emerging knowledge of the neuronal tRNA landscape, with a focus on epitranscriptomic tRNA modifications and downstream molecular pathways affected by alterations in tRNA expression, charging levels, and cleavage while mechanistically linking these pathways to neuropsychiatric disease and provide insight into future areas of study for this field.

Citing Articles

Neuron-Specific Glycine Metabolism Links Transfer RNA Epitranscriptomic Regulation to Complex Behaviors.

Blaze J, Evans V, Feria Pliego J, Unichenko P, Javidfar B, Heissel S Biol Psychiatry Glob Open Sci. 2025; 5(2):100432.

PMID: 39911537 PMC: 11794161. DOI: 10.1016/j.bpsgos.2024.100432.

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

Blaze J, Chen S, Heissel S, Alwaseem H, Landinez Macias M, Peter C Mol Psychiatry. 2025; .

PMID: 39809846 DOI: 10.1038/s41380-025-02891-8.

Comprehensive profiling of small RNAs and their changes and linkages to mRNAs in schizophrenia and bipolar disorder.

Nersisyan S, Loher P, Nazeraj I, Shao Z, Fullard J, Voloudakis G bioRxiv. 2025; .

PMID: 39763727 PMC: 11703252. DOI: 10.1101/2024.12.24.630254.

Stress-induced modification of tRNA generates 5-methylcytidine in the variable loop.

Valesyan S, Jora M, Addepalli B, Limbach P Proc Natl Acad Sci U S A. 2024; 121(46):e2317857121.

PMID: 39495928 PMC: 11572931. DOI: 10.1073/pnas.2317857121.

Epileptic encephalopathy linked to a DALRD3 missense variant that impairs tRNA modification.

Zhang K, Lohner K, Lemmink H, Boon M, Lentini J, de Silva N HGG Adv. 2024; 6(1):100377.

PMID: 39482881 PMC: 11615593. DOI: 10.1016/j.xhgg.2024.100377.

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