Dataset Information

Temporal proteomics of human cerebrospinal fluid reveals novel differentially-regulated proteins after severe traumatic brain injury

ABSTRACT: The pathophysiology of traumatic brain injury (TBI) requires further characterization to fully elucidate changes in molecular pathways. Cerebrospinal fluid (CSF) provides a rich repository of brain-associated proteins that may be affected by TBI. Here, we implemented high-resolution mass spectrometry to evaluate changes to the CSF proteome after severe TBI. 91 CSF samples were analyzed with mass spectrometry, collected from 16 patients with severe TBI (mean 32 yrs; 81% male) on day 0, 1, 2, 4, 7 and/or 10 post-injury (8-16 samples/timepoint) and compared to CSF obtained from 11 non-injured controls. We quantified 1152 proteins with mass spectrometry, of which approximately 80% were associated with CSF. 1083 proteins were differentially regulated after TBI compared to control samples. The most highly-upregulated proteins at each timepoint included neutrophil elastase, myeloperoxidase, cathepsin G, matrix metalloproteinase-8, and S100 calcium-binding proteins A8, A9 and A12—all proteins involved in neutrophil activation, recruitment, and degranulation. Pathway enrichment analysis confirmed the robust upregulation of proteins associated with innate immune responses. Conversely, downregulated pathways included those involved in nervous system development, and several proteins not previously identified after TBI such as testican-1 and latrophilin-1. We also identified 7 proteins (GM2A, Calsyntenin 1, FAT2, GANAB, Lumican, NPTX1, SFRP2) positively associated with an unfavorable outcome at 6 months post-injury. These findings highlight the robust innate immune response that occurs after severe TBI, supporting future studies to target neutrophil-related processes. In addition, the novel proteins we identified to be differentially regulated by severe TBI warrant further investigation as potential biomarkers or therapeutic targets.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

SUBMITTER: Ralf Schittenhelm

LAB HEAD: Bridgette Semple

PROVIDER: PXD035289 | Pride | 2023-03-11

REPOSITORIES: Pride

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Temporal proteomics of human cerebrospinal fluid after severe traumatic brain injury.

Shultz Sandy R SR Shah Anup D AD Huang Cheng C Dill Larissa K LK Schittenhelm Ralf B RB Morganti-Kossmann M Cristina MC Semple Bridgette D BD

Journal of neuroinflammation 20221208 1

The pathophysiology of traumatic brain injury (TBI) requires further characterization to fully elucidate changes in molecular pathways. Cerebrospinal fluid (CSF) provides a rich repository of brain-associated proteins. In this retrospective observational study, we implemented high-resolution mass spectrometry to evaluate changes to the CSF proteome after severe TBI. 91 CSF samples were analyzed with mass spectrometry, collected from 16 patients with severe TBI (mean 32 yrs; 81% male) on day 0, 1 ...[more]

PMID: 36482407

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Project description:Neurologic manifestations are among the most frequently reported complications of COVID-19. However, given the paucity of tissue samples and highly infectious nature of the etiologic agent of COVID-19, we have limited information to understand the neuropathogenesis of COVID-19. Therefore to better understand the impact of COVID-19 in brain, we employed mass-spectrometry-based proteomics using data-independent acquisition mode (DIA) to investigate cerebrospinal fluid (CSF) proteins collected from two different non-human primates, Rhesus Macaque and African Green Monkeys for the neurologic effects of the infection. These monkeys exhibited minimal to mild pulmonary pathology but moderate to severe CNS pathology. Our results indicate that CSF proteome changes after infection resolution correspond with bronchial virus abundance during early infection and revealed substantial differences between the infected NHPs and their age-matched uninfected controls, suggesting these differences could reflect altered secretion of CNS factors in response to SARS-CoV-2-induced neuropathology. We also observed the infected animals to exhibit much scattered data distributions as compared to the tightly clustered corresponding controls which suggest the heterogeneity of the CSF proteome change and the host response to the viral infection. In addition, dysregulated CSF proteins were preferentially enriched in functional pathways associated with progressive neurodegenerative disorders, hemostasis and innate immune responses that could influence neuroinflammatory responses following COVID-19. Mapping dysregulated proteins to the Human Brain Protein Atlas found that these proteins tended to be enriched in brain regions that exhibit more frequent injury following COVID-19. It therefore appears reasonable to speculate that such CSF protein changes could serve as signatures for neurologic injury, identify important regulatory pathways in this process, and potentially reveal therapeutic targets to prevent or attenuate the development of neurologic injuries following COVID-19.

Project description:Acute inflammatory demyelinating polyneuropathy (AIDP) - one of the forms of Guillain-Barre syndrome (GBS) - is a rare and severe disorder of the peripheral nervous system that also has an unknown etiology. One of the hallmarks of AIDP pathogenesis is a significantly elevated cerebrospinal fluid (CSF) protein level in comparison with the peptidome/proteome profile of a representative number of CSF samples obtained from AIDP and multiple sclerosis (MS) patients and control patients. In total, 2355 peptide fragments related to 795 proteins were found in CSF samples from AIDP patients, 1066 peptide fragments of 253 proteins in samples from MS patients, and 774 peptide fragments of 220 proteins from control patients. Proteomic studies detected 1103 proteins in the control cohort and 1402 proteins in the AIDP cohort. Our dataset suggests that the proteome of the CSF from AIDP and control patients overlaps by as much as 67%, whereas the peptidome is only 21.5% identical. Comparison of the peptidomic and proteomic data revealed that 80% of the peptides in the CSF of AIDP patients correspond to proteins that are not present in proteomic dataset. Importantly, a considerable number of differentially represented peptides are related to the proteins involved in the arrangement of the axonal domains. The observed peptidomic dataset indicates that specific proteins, which participate in the arrangement of the myelin sheath in the nodes of Ranvier, are degraded in the course of AIDP. Here, we show that the proteins that are overrepresented in the CSF of AIDP patients are partially linked with defensive responses to bacteria and viruses. These observations are in line with the upregulation of CSF cytokines associated with innate immunity, which in turn surprisingly suggests that the destruction of axons is not accompanied by any indications of a distinct adaptive autoimmune process. We believe that the presented proteomic and peptidomic dataset of the CSF from AIDP patients will provide useful information regarding the mechanisms of AIDP pathogenesis in comparison with MS, which is the prolonged but incurable autoimmune degradation of the central nervous system.

Dataset Information

Temporal proteomics of human cerebrospinal fluid reveals novel differentially-regulated proteins after severe traumatic brain injury

Publications

Temporal proteomics of human cerebrospinal fluid after severe traumatic brain injury.

Similar Datasets

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