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Extracellular Ezrin - a Novel Biomarker for Traumatic Brain Injury
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
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2015 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 32, no 4, 244-251 p.Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) is a heterogeneous disease, and the discovery of diagnostic and prognostic TBI biomarkers is highly desirable in order to individualize patient care. We have previously published a study in which we identified possible TBI biomarkers by mass spectrometry 24 h after injury in a cell culture model. Ezrin-radixin-moesin (ERM) proteins were found abundantly in the medium after trauma, and in the present study we have identified extracellular ezrin as a possible biomarker for brain trauma by analyzing cell culture medium from injured primary neurons and glia and by measuring ezrin in cerebrospinal fluid (CSF) from both rats and humans. Our results show that extracellular ezrin concentration was substantially increased in cell culture medium after injury, but that the intracellular expression of the protein remained stable over time. Controlled cortical impact injured rats showed an increased amount of ezrin in CSF at both day 3 and day 7 after trauma. Moreover, ezrin was present in all ventricular CSF samples from seven humans with severe TBI. In contrast to intracellular ezrin, which is distinctly activated following TBI, extracellular ezrin is nonphosphorylated. This is the first report of extracellular ERM proteins in human and experimental models of TBI, providing a scientific foundation for further assessment of ezrin as a potential biomarker.

Place, publisher, year, edition, pages
2015. Vol. 32, no 4, 244-251 p.
Keyword [en]
TBI, Moesin, Radixin, pERM, ERM, actin, extracellular proteins, astrocytes
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-215151DOI: 10.1089/neu.2014.3517ISI: 000349314900005PubMedID: 25087457OAI: oai:DiVA.org:uu-215151DiVA: diva2:686343
Available from: 2014-01-11 Created: 2014-01-11 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Cellular and Molecular Responses to Traumatic Brain Injury
Open this publication in new window or tab >>Cellular and Molecular Responses to Traumatic Brain Injury
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI) is a relatively unknown disease considering the tens of millions of people affected around the world each year. Many TBI patients die from their injuries and survivors often suffer from life-long disabilities. The primary injury initiates a variety of cellular and molecular processes that are both beneficial and detrimental for the brain, but that are not fully understood. The focus of this thesis has been to study the role of astrocytes in clearance of dead cells after TBI and to identify injury specific proteins that may function as biomarkers, by using cell cultures, animal models and in cerebrospinal fluid (CSF) from TBI patients.

The result demonstrates a new function in that astrocytes, the most numerous cell type in the brain, engulf dead cells after injury both in cell cultures and in adult mice and thereby save neurons from contact-induced apoptosis. Astrocytes are effective phagocytes, but degrade the ingested dead cells very slowly. Moreover, astrocytes express the lysosome-alkalizing proteins Rab27a and Nox2 as well as major histocompatibility complex class II, the receptors on which antigens are being presented. By lowering the pH of the lysosomes with acidic nanoparticles, the degradation increases, but the astrocytes still remained less effective than macrophages. Taken together, the data indicates that the low acidification in astrocytes can preserve antigens and that astrocytes may be able to activate T cells.

The expression and secretion of injury-specific proteins was studied in a cell culture model of TBI by separate mass spectrometry analysis of cells and medium. Interestingly, close to 30 % of the injury-specific proteins in medium are linked to actin, for example ezrin of the ezrin/radixin/moesin (ERM) protein family. Ezrin, but none of the other ERM proteins or actin, is actively secreted after injury. Extracellular ezrin also increases in CSF in response to experimental TBI in rats and is present in CSF from TBI patients, indicating that ezrin is a potential biomarker for TBI. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 966
Keyword
Traumatic Brain Injury, Astrocyte, Apoptosis, Biomarkers, Ezrin, Actin, Extracellular Proteins, Degradation, Lysosome, Antigen Presentation
National Category
Neurosciences
Research subject
Neuroscience; Neurosurgery
Identifiers
urn:nbn:se:uu:diva-215154 (URN)978-91-554-8845-1 (ISBN)
Public defence
2014-02-28, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Available from: 2014-02-06 Created: 2014-01-11 Last updated: 2014-02-10

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Lööv, CamillaHillered, LarsClausen, FredrikErlandsson, Anna

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