Novel Functions of Transfer RNA-Derived Fragments in the CNS
Overview
Transfer RNA-derived small RNAs (tsRNAs) are functional non-coding RNAs abundant in neurons and implicated in normal CNS function and neurological diseases. Disease-specific tsRNA profiles have been identified in disorders such as ALS, epilepsy, Alzheimer's, Parkinson's, and stroke, suggesting their potential as biomarkers and therapeutic targets.
Background
Transfer RNAs (tRNAs) traditionally function in protein translation by transporting amino acids. tsRNAs are cleavage products of tRNAs once thought to be degradation byproducts but are now recognized as regulatory molecules influencing transcription and translation. In the CNS, tsRNAs show cell type-specific expression, particularly in neurons, and their dysregulation is linked to neurological pathologies. Advances in sequencing technologies have facilitated the study of tsRNAs, revealing their diverse origins, biogenesis, and potential roles in brain health and disease.
Data Highlights
tsRNAs originate from both nuclear and mitochondrial tRNAs, with over 600 tRNA genes in humans but only a subset actively transcribed. Approximately 1% of parent tRNAs are cleaved into tsRNAs under stress conditions. Specific nucleases such as angiogenin generate distinct tsRNA types, including tRNA halves and shorter fragments. Disease-specific tsRNA signatures have been detected in blood, cerebrospinal fluid, and brain tissues correlating with neurological disorders and cognitive decline.
Key Findings
tsRNAs are abundant in neurons and exhibit cell type-specific expression profiles in the CNS.
Disease-specific tsRNA profiles have been identified in ALS, epilepsy, Alzheimer's disease, Parkinson's disease, and ischemic stroke.
Elevated tsRNA levels in blood can precede epileptic seizures, indicating potential as early biomarkers.
Age- and sex-specific loss of mitochondrial tsRNAs in the nucleus accumbens correlates with accelerated cognitive decline in Alzheimer's disease.
tsRNAs modulate gene expression via miRNA-like targeting of mRNAs, interaction with RNA-binding proteins, and interference with translation machinery.
Chemical modifications inherited from parent tRNAs influence tsRNA production and function.
Clinical Implications
The identification of disease-specific tsRNA signatures in accessible fluids such as blood and cerebrospinal fluid offers promising avenues for early diagnosis and monitoring of neurological disorders. Understanding tsRNA mechanisms may enable development of novel therapeutics targeting these molecules to modulate neuronal function and neurodegeneration in an age- and sex-specific manner.
Conclusion
tsRNAs represent a novel class of regulatory RNAs with significant roles in CNS physiology and pathology. Continued research into their biogenesis, function, and disease associations may unlock new diagnostic and therapeutic strategies for brain disorders.
References
Transfer RNA-derived small RNAs in CNS -- Review Article
