Abstract
Acute spinal cord injury (SCI) is a devastating condition with many consequences and no known effective treatment. Although it is quite easy to diagnose traumatic SCI, the assessment of injury severity and projection of disease progression or recovery are often challenging, as no consensus biomarkers have been clearly identified. Here rats were subjected to experimental moderate or severe thoracic SCI. At 24h and 7d postinjury, spinal cord segment caudal to injury center versus sham samples was harvested and subjected to differential proteomic analysis. Cationic/anionic-exchange chromatography, followed by 1D polyacrylamide gel electrophoresis, was used to reduce protein complexity. A reverse phase liquid chromatography-tandem mass spectrometry proteomic platform was then utilized to identify proteome changes associated with SCI. Twenty-two and 22 proteins were up-regulated at 24 h and 7 day after SCI, respectively; whereas 19 and 16 proteins are down-regulated at 24 h and 7 day after SCI, respectively, when compared with sham control. A subset of 12 proteins were identified as candidate SCI biomarkers - TF (Transferrin), FASN (Fatty acid synthase), NME1 (Nucleoside diphosphate kinase 1), STMN1 (Stathmin 1), EEF2 (Eukaryotic translation elongation factor 2), CTSD (Cathepsin D), ANXA1 (Annexin A1), ANXA2 (Annexin A2), PGM1 (Phosphoglucomutase 1), PEA15 (Phosphoprotein enriched in astrocytes 15), GOT2 (Glutamic-oxaloacetic transaminase 2), and TPI-1 (Triosephosphate isomerase 1), data are available via ProteomeXchange with identifier PXD003473. In addition, Transferrin, Cathepsin D, and TPI-1 and PEA15 were further verified in rat spinal cord tissue and/or CSF samples after SCI and in human CSF samples from moderate/severe SCI patients. Lastly, a systems biology approach was utilized to determine the critical biochemical pathways and interactome in the pathogenesis of SCI. Thus, SCI candidate biomarkers identified can be used to correlate with disease progression or to identify potential SCI therapeutic targets.
Highlights
Acute spinal cord injury (SCI) is a devastating condition with many consequences and no known effective treatment
A subset of 12 proteins were identified as candidate SCI biomarkers - TF (Transferrin), FASN (Fatty acid synthase), NME1 (Nucleoside diphosphate kinase 1), STMN1 (Stathmin 1), EEF2 (Eukaryotic translation elongation factor 2), CTSD (Cathepsin D), ANXA1 (Annexin A1), ANXA2 (Annexin A2), PGM1 (Phosphoglucomutase 1), PEA15 (Phosphoprotein enriched in astrocytes 15), GOT2 (Glutamic-oxaloacetic transaminase 2), and TPI-1 (Triosephosphate isomerase 1), data are available via ProteomeXchange with identifier PXD003473
It has been hypothesized that the pathologic process that leads to acute traumatic spinal cord injury consists of two steps; the primary injury is the physical and mechanical damages that occur as a result of direct impact to the spinal cord
Summary
Moghieb, Ahmed; Bramlett, Helen M.; Das, Jyotirmoy H.; Yang, Zhihui; Selig, Tyler; Yost, Richard A.; Wang, Michael S.; Dietrich, W. Spinal Cord Injury Differential Proteomic Study cannot assess the severity of SCI; in addition, the neurological recovery variability for SCI patients is high. Calcium binding protein S100 beta (S100), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), neuron specific enolase (NSE), neurofilament protein- H and L (NF-H, NF-L), SBDP150/SBDP145/SBDP120, ubiquitin C-terminal hydrolase-L1 (UCHL-1), microtubule- associated 2 (MAP-2), and cytokines interleukins 6 and 8 (IL-6 and IL-8) have been identified as potential markers of spinal cord damage mainly in the cerebrospinal fluid (CSF) compartment (6, 26 –36) These studies need to be developed and validated for their potential use in clinical settings to determine the severity of SCI. We sough to identify possible new SCI markers by using our CAX-PAGE-LC-MS/MS proteomic platform [41] using SCI biosamples collected from both an SCI animal model (weight-drop) and human clinical studies of SCI patients
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