Emerging roles of transfer RNA fragments in the CNS

Abstract tRNA-derived small RNAs (tsRNAs), previously considered inactive tRNA degradation products, have now been shown to be functional small noncoding RNAs. They may play important roles within the central nervous system (CNS) and in brain-body interactions both during normal developmental stages as well as in diverse brain pathologies. Among the cell types found in the CNS, tsRNAs are most abundant in neurons. Correspondingly, neurons show cell type specific tRNA expression profiles when compared to other cells of the CNS under homeostatic conditions and defects in tRNA processing may lead to neurological disorders. Disease-specific tsRNA profiles have been identified in a number of CNS disorders including amyotrophic lateral sclerosis (ALS) and epilepsy. Elevated levels of specific tsRNAs have been found in the blood before the onset of epileptic seizures, and age-related, sex-specific loss of mitochondrial genome-originated tsRNAs in the nucleus accumbens of female patients is correlated to accelerated cognitive deterioration in Alzheimer’s disease. Disease-related tsRNA signatures have also been identified in the cerebrospinal fluid of Parkinson’s disease patients, and nucleated blood cells from ischemic stroke patients show specific elevation of cholinergic-targeted tsRNAs. The mechanisms of action of tsRNAs are still being elucidated but include targeting complementary mRNA to impact RNA levels and translation in a miRNA-like manner, direct interaction with RNA binding proteins, or interference with translation machinery. The function of tsRNAs may be affected by the chemical modifications they inherit from the originating tRNA molecules, which impact tsRNAs production and may modulate their interactions with proteins. Research on the genetics, biochemical properties and regulatory roles of tsRNAs has expanded rapidly in recent years, facilitated by novel sequencing strategies which include the removal of tRNA modifications and chemically blocked ends that hinder amplification and adapter ligation. Future in-depth profiling of tsRNAs levels, mode/s of function, and identification of interacting proteins and RNAs may together shed light on the tsRNAs impact on neuronal function, and enable novel diagnostics/therapeutics avenues for brain diseases in age, sex and disease-specific manner.