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Diagnostic marker development of tRNA-derived fragments in cerebrospinal fluid and blood serum

ABSTRACT: The development of non-invasive diagnostic methods is crucial in early disease detection and thus better treatment options. Small RNAs have been identified as good candidates for such diagnostic markers due to their small size, which allows ease of transport from live cells. Correlating small RNAs in bodily fluid with those in tissue cells of interest may even shed light on disease mechanisms and the development of therapeutic targets. tRNA-derived RNA fragments (tRFs), a family of recently discovered small non-coding RNAs (sncRNAs), have been found to be significantly changed in various disease states, including Alzheimer's disease (AD), the most common type of dementia. Previously, tRFs have been found to be significantly enhanced in human AD hippocampus tissues. However, whether tRFs change in body fluids is unknown. In this study, we planned to identify baselines for potential usage of tRFs as biomarkers in cerebrospinal fluid and blood serum for future development of AD biomarkers. Towards this goal, we used T4 polynucleotide kinase-RNA-seq, a modified next-generation sequencing technique, to identify detectable tRFs in human cerebrospinal fluid (CSF) and serum samples. Interestingly, we found an abundance of tRFs in both CSF and serum samples in comparison to microRNAs, well-known small RNAs (about 3-10 times higher in read counts). This clearly indicates the significant potential of tRFs as non-invasive biomarkers in CSF and serum.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241686 | GEO | 2023/12/01

REPOSITORIES: GEO

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Project description:s synapse degeneration is an early event in Alzheimer’s disease (AD) pathophysiology, a biofluid marker of synapse loss in living patients could be a surrogate marker of disease prognosis and therefore would be an excellent addition to the AD biomarker arsenal. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins that could be potential biomarkers of underlying synapse degeneration. The aim of this study was to identify, verify and evaluate a set of synaptic proteins as surrogate CSF markers of underlying synapse loss in AD patients. In the Discovery Stage, we combined high-throughput shotgun proteomics of the CSF with an exhaustive search of the literature and public databases for proteomic studies of the CSF and synapse. A thorough characterization of the synaptic component of the CSF identified 210 synaptic proteins that are detectable in human CSF. We selected an initial panel of 22 candidate biomarkers for evaluation. In the Verification Stage, 12 proteins were discarded due to poor detection by targeted mass spectrometry (Selected Reaction Monitoring, SRM). We confirmed the expression of the remaining 10 proteins either directly at (Calsynytenin-1, GluR2, GluR4, Neurexins 2A and 3A, Neuroligin-2, Syntaxin-1B, Thy-1 and Vamp-2), or surrounding (Tenascin-R), the human synapse using Array Tomography microscopy and biochemical fractionation methods. We quantified the synaptic panel by SRM in CSF samples from 2 independent clinical cohorts of cognitively normal controls and all clinical stages of AD (n=140). A set of the panel proteins demonstrated a non-linear profile distinct to that of existing biomarkers whereby the CSF levels were decreased at the earliest preclinical stage of AD, reflecting reduced synaptic density in these asymptomatic individuals and elevated at later symptomatic stages when neurodegeneration is widespread. In conclusion, we have identified a set of novel synapse-specific proteins that could have clinical value for assessing disease progression in individuals at-risk for AD and potentially in other neurological disorders characterized by early synapse loss.

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Diagnostic marker development of tRNA-derived fragments in cerebrospinal fluid and blood serum

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