Molecular messengers of the brain: tRNA-derived small RNAs at the crossroads of brain development and neurodevelopmental disorders

Brain development is tightly regulated by different modulators and mechanisms. Disruptions in these processes underlie a spectrum of neurodevelopmental disorders. Among non-coding RNAs, which usually act as key regulators of brain development, tRNA-derived small RNAs (tsRNAs) have recently emerged as functional regulators, rather than mere degradation byproducts. Abundantly and dynamically expressed in the brain, tsRNAs influence translation, epigenetics, and RNA-protein interactions, suggesting roles in neurogenesis, synaptic development, and synaptic plasticity. This review synthesizes current knowledge on tsRNA biogenesis, classification, and molecular functions, with a particular focus on their roles in brain development and neurodevelopmental disorders. We highlight how tsRNAs may act as modulators, serve as potential biomarkers, and represent novel therapeutic targets in these conditions. By integrating emerging findings and identifying key knowledge gaps, we aim to establish tsRNAs as pivotal players in both brain health and disease.