Evidence linking microRNA suppression of essential prosurvival genes with hippocampal cell death after traumatic brain injury

Boone, Deborah Kennedy; Weisz, Harris A.; Bi, Min; Falduto, Michael T.; Torres, Karen E.O.; Willey, Hannah E.; Volsko, Christina; Kumar, Anjali; Micci, Maria‐Adelaide; DeWitt, Douglas S.; Prough, Donald S.; Hellmich, Helen L.

doi:10.1038/s41598-017-06341-6

Cited by 22 publications

(27 citation statements)

References 46 publications

(57 reference statements)

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“…In the brain, altered miRNA expression is linked to neurodegenerative disorders 5 . In previous rat TBI studies, we reported that 24 h after experimental TBI, injury-induced miRNAs suppressed expression of pro-survival genes in dying hippocampal neurons 6 . These miRNA target genes, according to the Online Mendelian Inheritance in Man (OMIM) database, lead to human disease when dysregulated, mutated or deleted 7 .…”

Section: High-throughput Sequencing Technologies Could Improve Diagnomentioning

confidence: 89%

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

Weisz

Kennedy

Widen

et al. 2020

Sci Rep

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age-matched control serum. In these exploratory studies with rat and human tissues, we tested three hypotheses, 1) miRNA-seq profiles would identify TBI at all acute and chronic post-injury intervals, 2) miRNA-seq profiles would discriminate between focal and diffuse TBI and 3) serum miRNA-seq would reveal potential miRNA markers of neuropsychiatric and neurodegenerative sequelae. Methods Study design. The miRNA-seq and data analyses workflow is shown in Fig. 1A (rat studies) and Fig. 2A (human studies). Detailed methods, including rat surgical procedures, are described in Supplementary Materials and are summarized below. All procedures were done under a protocol (No. 1312056A) approved by the University of Texas Medical Branch at Galveston's Institutional Animal Care and Use Committee. All procedures performed as part of this study were performed in accordance with institutional, state, and U.S. federal guidelines and regulations. In the rat studies, for each post-injury interval, we sequenced four TBI and four sham-control hippocampi, thus 56 rats were used for miRNA-seq analysis. In the human studies, we sequenced 51 serum samples (six acute and six aged controls, 33 acute TBI representing 24, 48, 96 h post-injury, six chronic TBI [2-32 years post-injury]). Demographic characteristics are shown in Table 1. Rat hippocampus and serum isolation and PCR array analysis. Total RNA from rat hippocampal tissue was extracted and purified using Ribopure (Ambion) as in Boone and Weisz et al. 9. Serum from rats subjected to FPI and CCI was used for miRNA isolation and PCR array analysis as described in Supplementary Methods.

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Section: High-throughput Sequencing Technologies Could Improve Diagnomentioning

confidence: 89%

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

Weisz

Kennedy

Widen

et al. 2020

Sci Rep

Self Cite

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“…By performing a motifs search on all DMRs, we identified 14 TF motifs ( Table 1) that were significantly enriched in agerelated DMRs in both the blood and brain suggesting potential translational relevance of the findings from this study. Six of those 14 common motifs (ELK1, ELF1, ETV1, ETV4, ETV5, RXR) have been associated with modulating synaptic density, arborization, and neurite outgrowth (Gao et al, 1996;Abe et al, 2011;Szatmari et al, 2013;Boone et al, 2017). Furthermore, ETV1, ELK1, EAR2, RXR, and GABPA have been implicated in regulating cognitive function.…”

Section: Discussionmentioning

confidence: 99%

Age-Associated DNA Methylation Patterns Are Shared Between the Hippocampus and Peripheral Blood Cells

et al. 2020

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As the population ages, interest in identifying biomarkers of healthy aging and developing antiaging interventions has increased. DNA methylation has emerged as a potentially powerful molecular marker of aging. Methylation changes at specific sites in the human genome that have been identified in peripheral blood have been used as robust estimators of chronological age. Similar age-related DNA methylation signatures are also seen in various tissue types in rodents. However, whether these peripheral alterations in methylation status reflect changes that also occur in the central nervous system remains unknown. This study begins to address this issue by identifying age-related methylation patterns in the hippocampus and blood of young and old mice. Reducedrepresentation bisulfite sequencing (RBSS) was used to identify differentially methylated regions (DMRs) in the blood and hippocampus of 2-and 20-month-old C57/Bl6 mice. Of the thousands of DMRs identified genome-wide only five were both found in gene promoters and significantly changed in the same direction with age in both tissues. We analyzed the hippocampal expression of these five hypermethylated genes and found that three were expressed at significantly lower levels in aged mice [suppressor of fused homolog (Sufu), nitric oxide synthase 1 (Nos1) and tripartite motif containing 2 (Trim2)]. We also identified several transcription factor binding motifs common to both hippocampus and blood that were enriched in the DMRs. Overall, our findings suggest that some agerelated methylation changes that occur in the brain are also evident in the blood and could have significant translational relevance.

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“…Previous studies indicated that MSCs promised to be an effective therapy for brain injury in TBI [175-177, 215, 231-236]. Instead of brain remodeling and functional recovery by cell replacement effects, evidence suggests that the major effects of neurorestoration were due to the paracrine effects of secretion-based factors such as MSCs-derived exosomes that may reduce neuroinflammation, promote neurogenesis and angiogenesis, rescue pattern separation and spatial learning impairments, and improve functional recovery after TBI in animal models [107,176,178,191,204,205,215,216,[235][236][237]. In addition, as exosomes contain various miRNAs, which play a key role in modifying the phenotype and/or the physiology and modulating the cellular processes of the recipient cell, and miRNAs such as miR-21 could be potential therapeutic targets for interventions after TBI, the combination of miRNAs and MSC-derived exosomes might be a novel approach for the treatment of TBI [238].…”

Section: Extracellular Vesicles and Exosomesmentioning

confidence: 99%

“…MSCs have shown promise in the field of regenerative medicine, since exogenously administered MSCs target injured tissue, interact with brain parenchymal cells, and promote neurorestoration and recovery of neurological function after brain injuries [178,191,204,205]. Despite the differentiation capacity of MSCs, the principal mechanism of their therapeutic action seems to be a robust paracrine capacity, related to their soluble factors as well as generation and release of microvesicles and exosomes [178,205].…”

Section: Extracellular Vesicles and Exosomesmentioning

confidence: 99%

“…Bioinformatic and gene ontology analyses revealed 107 putative target genes, as well as several biological processes that might be initiated by the dysregulated miRNAs, that include miR-144, miR-153, and miR-340-5p. Recently, a study analyzed the biological roles of about 600 genes that are targeted by 10 TBI-altered miRNAs [191]. Bioinformatic analysis suggested that neurodegeneration results from a global miRNA-mediated suppression of genes essential for maintaining proteostasis, the competing and integrated biological pathways that control the synthesis, folding, trafficking, and degradation of proteins.…”

Section: Micrornasmentioning

confidence: 99%

See 1 more Smart Citation

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

Regner¹,

Meirelles²,

Simon³

2018

Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

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Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Understanding the pathophysiology of TBI is crucial for the development of more effective therapeutic strategies. At the moment of the traumatic impact, transfer of kinetic forces causes neurologic damage; this primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes, called secondary neural injury. These areas of ongoing secondary injury, or areas of "traumatic penumbra," represent crucial targets for therapeutic interventions. This chapter is focused on the interplay between progression of parenchymal injury and the neuroprotective and neurorestorative processes that are emerging and developing subsequently to traumatic impact. Thus, we emphasized the role of traumatic penumbra in TBI pathogenesis and suggested a crucial contribution of the neurovascular units (NVUs) and paracrine effects of exosomes and miRNAs in promoting neurological recovery.

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Evidence linking microRNA suppression of essential prosurvival genes with hippocampal cell death after traumatic brain injury

Cited by 22 publications

References 46 publications

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

Age-Associated DNA Methylation Patterns Are Shared Between the Hippocampus and Peripheral Blood Cells

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

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