Transfer RNA fragments: the Phoenix non-coding small RNA regulators of cholinergic networks

Seeking the role[s] of small non-coding RNAs in mammalian cholinergic regulation, we currently study transfer RNA fragments (tRFs). Initially considered obsolete degradation products of tRNAs and their precursors, tRFs recently emerged as vital ‘phoenix’ controllers that rise from the ashes of tRNAs and affect brain-body interactions in diverse age and disease states. In ischemic stroke patients’ nucleated blood cells, cholinergic-targeted microRNAs are exchanged by tRFs (Winek et al., PNAS 2020). In women Alzheimer’s disease (AD) brains, accelerated cognitive decline reflects the loss of cholinergic-targeted mitochondrial genome-originated tRFs in the nucleus accumbens (Shulman et al., Alzheimer&Dementia 2023). Further, brain accumulation of the longevity protein Klotho accompanies altered AD-related profiles and chemical pseudo-uridine modifications of neuronal tRFs (Dubnov et al., Communication Biology 2024); intriguingly, altered Parkinson’s disease(PD) profiles of cerebrospinal fluid tRFs (Paldor et al., J Neurochem 2022) accompany brain and blood amplification of numerous tRFs carrying a shared internal 7 nucleotides motif, whose levels escalate long before PD tremor symptoms but decline under deep brain stimulation (Madrer et al., under review). Moreover, altered profiles of tRFs families in the fetal umbilical cord serum, especially of female fetuses reflect the pre-delivery stress to which their mothers were exposed (Vaknin et al., submitted). Profiled brain and blood tRFs, their modes of action, interacting proteins and RNA partners along age and in diverse health situations can hence reveal the multi-leveled impact of tRFs on cholinergic networks and their structure-function links while opening new venues for future diagnostics and therapeutics of diverse brain diseases.