Discovering novel diagnostic biomarkers and signatures for traumatic brain injury (TBI) represents a major challenge in the brain trauma research. Detailed analysis of post-concussive molecular pathways based on experimental data could provide a new insight into the pathophysiological sequelae and mapping of recovery mechanisms involved in TBI. MicroRNAs (miRNAs) detectable in peripheral body fluids after TBI are promising carriers of this missing knowledge. In order to define the signature of peripheral miRNAs signaling associated with mild TBI (mTBI), we performed a comprehensive meta-analysis of miRNA profiles in mTBI patients using multiple curated pathway databases. Using a bioinformatic pipeline with integrated data analysis we identified a set of genes that are connected to deregulated circulating miRNAs following the mTBI. Identified genes belong to specific pathways of MAPK, TGF-β, WNT, TLR2/4, PI3K/AKT, insulin, and growth factor signaling. Since the enriched pathways markedly overlap among the various biological fluids, signaling associated with mTBI that is concomitantly reflected in serum, plasma and saliva is robust and unique. Furthermore, we identified a network of 33 validated interacting proteins and their regulatory miRNAs that link the post-mTBI signaling in peripheral fluids with neurodegenerationassociated interaction pathways. Presented data provide a comprehensive insight into molecular events following mTBI, and the top predicted genes represent a group of novel candidate targets to be validated in connection with mTBI.
Repetitive concussive head impacts and their harmful consequences described in the brains of contact sports players represent a major risk factor for development of chronic traumatic encephalopathy. However, the molecular events together with peripheral markers of repetitive head impacts were not fully elucidated to date. As soccer is one of the contact sports with a high risk of head injuries, this study focused on the altered expression level of circulating microRNAs (miRNAs) in soccer players following accidental head impacts and repetitive heading the ball, accounting for the effects of physical activity alone. Furthermore, the study aimed to define the associations between detected miRNAs and signaling pathways. The current study was based on a subset of blood samples available from a prospective cohort study by Straume‐Næsheim et al., 2008 and 2009 assessing the effects of head impacts in senior elite soccer on neuropsychological tests and serum protein biomarkers (PMID: 18824996, 19349829). Blood samples of professional soccer players were drawn at the rest and then repeatedly after three conditions: (1) accidental head impacts in a match, (2) repetitive heading during training, and (3) high‐intensity exercise. Altered levels of circulating miRNAs were obtained by real‐time PCR. Using bioinformatic approaches, we identified the predicted miRNA gene targets and their roles in biological pathways. We found six miRNAs implicated in the repetitive heading, unaffected by high‐intensity exercise, and eight miRNAs in the accidental head impacts. MiRNA gene targets were subsequently linked to overlapping, as well as unique signaling pathways for each of the studied conditions. These findings suggest that concussive and sub‐concussive head impacts in soccer cause specific alterations in circulating microRNAs that are unaffected by high‐intensity exercise.
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