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Global proteomic analysis of extracellular matrix in mouse and human brain highlights association with cerebrovascular disease

ABSTRACT: The extracellular matrix (ECM), a key interface between the cerebrovasculature and other cells within the neuro-glial-vascular unit , provides structural stability and modulates cell behaviour and signalling. These functions are dependent on ECM protein composition. Since ECM defects may contribute to a broad range of disorders including cerebrovascular disease, it is crucially important to characterize ECM composition to better understand the mechanisms by which the ECM modulates brain health and disease. To date, molecular studies of the cerebrovascular ECM have been limited. We therefore generated ECM extracts from vascular enriched tissues of both mouse and human post-mortem brain. We used mass spectrometry with off-line high-pH reversed-phase fractionation to increase proteome depth and characterized the identified proteins. This identified a large number of proteins (>1000 mouse, >2000 human) in the ECM-enriched fractions, with > 66% of the identified proteins covered in both human and mouse samples. We now report 147 ECM proteins, including collagens (as major ECM components), laminins, fibronectin and nidogens, that can be considered as the core constituents of the human brain vascular matrisome. We also identified 12 novel proteins in the ECM-enriched fraction, that may have regulate or interact with the matrisome, including several key regulators of neurovascular interactions, such as BCAM, CDH5 and PARVB. Many of the identified brain vascular matrisome proteins are encoded by genes identified in stroke and cerebral small vessel disease genome-wide association studies, underscoring the importance of the vascular ECM in health and disease. This brain vascular matrisome represents a powerful resource for investigating the impact of aging and disease on the cerebrovasculature.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Raphael A Heilig

LAB HEAD: Roman Fischer

PROVIDER: PXD020436 | Pride | 2021-03-11

REPOSITORIES: Pride

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Project description:Cerebral malaria (CM) is a severe complication of a Plasmodium falciparum infection and is still responsible for a high number of deaths and long term disabilities in children in sub-Saharan Africa. The pathogenesis of this syndrome remains incompletely understood but a number of mechanisms and effectors have been proposed, including plasma microparticles (MP). These submicron vesicles released by potentially all cells carry proteins and nucleic acids derived from the mother cell. In CM, their numbers are increased in patients’ circulation and, in the mouse model, they can be localised within inflamed vessels, suggesting their involvement in vascular damage. In the present work we define, for the first time, the protein cargo of MP during experimental cerebral malaria (ECM) with the overarching hypothesis that characterising this content could help in better understand CM pathogenesis. Using qualitative and quantitative high-throughput proteomics we compared MP proteins from non-infected mice and mice infected with P. berghei ANKA at two different stages of infection, i.e., pre-clinical phase and full blown syndrome. Overall, we identified 368 proteins, 60 of which were differentially expressed, as determined by quantitative comparison using the TMT® isobaric labelling. The analysis with Ingenuity® IPA highlighted important networks significantly represented among the proteins over-expressed (n=42) or identified only (n=21) in ECM, comprising mechanisms already proposed to be involved in CM, such as endothelial activation. Two proteins of interest, carbonic anhydrase I (CA-I) and S100A8, were verified by western blot on newly collected MP samples from DBA/1 (n=16) and C57BL/6 (n=8) mice, and confirmed to be associated with ECM MP. These results demonstrate that MP protein cargo represents a novel ECM pathogenic trait to consider in the understanding of CM pathogenesis. The identification of the cellular source of MP containing proteins associated to the disease state will contribute to further understanding their involvement in CM.

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Global proteomic analysis of extracellular matrix in mouse and human brain highlights association with cerebrovascular disease

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