Abstract
History of traumatic brain injury (TBI) represents a significant risk factor for development of dementia and neurodegenerative disorders in later life. While histopathological sequelae and neurological diagnostics of TBI are well defined, the molecular events linking the post-TBI signaling and neurodegenerative cascades remain unknown. It is not only due to the brain’s inaccessibility to direct molecular analysis but also due to the lack of well-defined and highly informative peripheral biomarkers. MicroRNAs (miRNAs) in blood are promising candidates to address this gap. Using integrative bioinformatics pipeline including miRNA:target identification, pathway enrichment, and protein–protein interactions analysis we identified set of genes, interacting proteins, and pathways that are connected to previously reported peripheral miRNAs, deregulated following severe traumatic brain injury (sTBI) in humans. This meta-analysis revealed a spectrum of genes closely related to critical biological processes, such as neuroregeneration including axon guidance and neurite outgrowth, neurotransmission, inflammation, proliferation, apoptosis, cell adhesion, and response to DNA damage. More importantly, we have identified molecular pathways associated with neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases, based on purely peripheral markers. The pathway signature after acute sTBI is similar to the one observed in chronic neurodegenerative conditions, which implicates a link between the post-sTBI signaling and neurodegeneration. Identified key hub interacting proteins represent a group of novel candidates for potential therapeutic targets or biomarkers.
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Abbreviations
- sTBI:
-
Severe traumatic brain injury
- AD:
-
Alzheimer’s disease
- miRNA:
-
MicroRNA
References
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Funding
Bioinformatic analyses were in part supported by the Ministry of Education of the Slovak Republic, awarded to BrainTest, s.r.o. within the research scheme “Stimuli for research and development” and research grants VEGA 2/0118/19, VEGA 2/0153/22, APVV-17-0668, APVV-19-0568, APVV-20-0615, and ERA-NET Neuron Neu-Vasc, CIHR-Eranet Neuron (NOD-168163), Ontario Research Fund (RDI 34876), and Canada Foundation for Innovation (CFI 29272, 225404, 33536).
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KM, NC, and SP collected and curated the data. YN and IJ performed the bioinformatic analysis. MC and KM wrote the manuscript. PF, AT, MM, and IJ reviewed and edited the manuscript. All authors read and approved the final version of the manuscript.
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10571_2022_1254_MOESM1_ESM.png
Supplementary file1 (PNG 20240 kb)—Target genes for deregulated miRNAs in serum and CSF after sTBI, as identified in mirDIP. Node color for genes represents Gene ontology (GO) molecular function, and node outline for miRNAs highlights experimental evidence, as per legend. Listed gene names are targeted by most of the deregulated miRNAs, and names with green background highlight genes regulated by validated miRNAs
10571_2022_1254_MOESM2_ESM.png
Supplementary file2 (PNG 5614 kb)—Target genes for deregulated miRNAs in plasma and CSF after sTBI, as identified in mirDIP. Node color for genes represents Gene ontology (GO) molecular function, and node outline for miRNAs highlights experimental evidence, as per legend. Listed gene names are targeted by most of the deregulated miRNAs, and names with green background highlight genes regulated by validated miRNAs
10571_2022_1254_MOESM3_ESM.png
Supplementary file3 (PNG 12328 kb)—Target genes for deregulated miRNAs in serum and plasma after sTBI, as identified in mirDIP. Node color for genes represents Gene ontology (GO) molecular function, and node outline for miRNAs highlights experimental evidence, as per legend. Listed gene names are targeted by most of the deregulated miRNAs, and names with green background highlight genes regulated by validated miRNAs
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Cente, M., Matyasova, K., Csicsatkova, N. et al. Traumatic MicroRNAs: Deconvolving the Signal After Severe Traumatic Brain Injury. Cell Mol Neurobiol 43, 1061–1075 (2023). https://doi.org/10.1007/s10571-022-01254-z
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DOI: https://doi.org/10.1007/s10571-022-01254-z