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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:HIGHTLIGHTS-Improved protocol for ISF collection using microdialysis and CSF sampling in mice.-Combined LC‒MS/MS proteomics ISF and CSF analyses for the validation and description of potential new AD biomarkers.-ISF proteomics analysis to track disease progression at the neuronal and glial levels.-Identification of new biomarker candidates for Alzheimer’s disease.ABSTRACTBackground: Mass spectrometry (MS)-based cerebrospinal fluid (CSF) proteomics is an important method for discovering biomarkers of neurodegenerative diseases. CSF serves as a reservoir for interstitial fluid (ISF), and extensive communication between the two fluid compartments helps to remove waste products from the brain.New method: We performed proteomic analyses of both CSF and ISF fluid compartments using intracerebral microdialysis to validate and detect novel biomarkers of Alzheimer's disease (AD) in APPtg and C57Bl/6J control mice.Results: We identified up to 625 proteins in ISF and 4,483 proteins in CSF samples. By comparing the biofluid profiles of APPtg and C57Bl/6J mice, we detected 37 and 108 significantly up- and downregulated candidates, respectively. In ISF, 7 highly regulated proteins, such as Gfap, Aldh1l1, Gstm1, and Txn, have already been implicated in AD progression, whereas in CSF, 9 out of 14 highly regulated proteins, such as Apba2, Syt12, Pgs1 and Vsnl1, have also been validated to be involved in AD pathogenesis. In addition, we also detected new interesting regulated proteins related to the control of synapses and neurotransmission (Kcna2, Cacng3, and Clcn6) whose roles as AD biomarkers should be further investigated.Comparison with existing methods: This newly established combined protocol provides better insight into the mutual communication between ISF and CSF as an analysis of tissue or CSF compartments alone.Conclusions: The use of multiple fluid compartments, ISF and CSF, for the detection of their biological communication enables better detection of new promising AD biomarkers.KEYWORDSAlzheimer’s disease, CSF, ISF, proteomics, biomarkers, microdialysis, mass spectrometry, protein identification, neurodegeneration, brain fluids, expression profilesDATA AVAILABILITYDOI: 10.17605/OSF.IO/VWQ58PUBLICATIONS using this dataset:1)Gorska et al. 2024, Journal of Neuroscience Methodshttps://doi.org/10.1016/j.jneumeth.2024.1102392) to come

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

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