Cerebrospinal fluid and blood profiles of transfer RNA fragments show age, sex and Parkinson’s disease-related changes

Abstract

Transfer RNA fragments (tRFs) have recently been shown to be an important family of small regulatory RNAs with diverse functions. Recent reports have revealed modified tRF blood levels in a number of nervous system conditions including epilepsy, ischemic stroke and neurodegenerative diseases, but little is known about tRF levels in the cerebrospinal fluid (CSF). To address this issue, we studied age, sex and Parkinsons disease (PD) distributions of tRFs in the CSF and blood data of PD patients and healthy controls from the NIH and the PPMI small RNA-seq datasets. The higher levels of long tRFs were found in the CSF than in the blood. Furthermore, the CSF showed pronounced age-associated declines of the level of 3prime-tRFs and i-tRFs and more pronounced differences between the sexes. Blood showed moderate elevation of 3prime-tFs levels with age. In addition, different distinct sets of tRFs segregated PD patients from controls in the CSF and in the blood. Finally, we found enrichment of tRFs predicted to target cholinergic mRNAs (Cholino-tRFs) in the mitochondrial originated tRFs, raising the possibility that the neurodegeneration-related mitochondrial impairment may lead to deregulation of cholinergic tone. Our findings suggest that CSF expressed tRFs are not a mirror of blood tRFs but rather potentially reflect the cerebral changes. Further, both CSF and blood present modified levels of tRFs in a sex-, age-and disease-related manner, calling for including this important subset of small RNA regulators to future studies.

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer’s disease

“…Additionally, studies identified MT-tRFs as key regulators in nuclear-mitochondrial communication 90 , which is dysfunctional in many neurodegenerative diseases, including AD. Notably, our finding of an association between tRFs of mitochondrial origin that carry motifs complementary to those of cholinergic transcripts, resemble the enrichment in sequence-based motifs to cholinergic transcripts in MT-tRFs from the cerebrospinal fluid (CSF) and blood of donors with Parkinson's Disease (PD) 91 . These results suggest that the mitochondrial damage seen in neurodegenerative disorders such as PD 92 and AD 15 is linked to failed regulation of cholinergic targets by CholinotRFs, and potentially to a broader cholinergic and mitochondrial linked defect in sncRNAs at large.…”