The tRNA regulome in neurodevelopmental and neuropsychiatric disease

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^Gly) 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.