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Plasma proteome profiling to assess human health and disease

ABSTRACT: Proteins in the circulatory system mirror an individual´s physiology. They are easy to obtain and consequently, plasma and serum are the predominant matrices for diagnostic analyses in daily clinical practice. Protein levels are generally determined using single protein immuno-assays. Mass spectrometry (MS)-based proteomics of this body fluid is challenging due to the high dynamic range of protein abundances. Here we introduce a rapid and robust single-run proteomic workflow that enables the quantitative analysis of hundreds of plasma proteomes from single finger pricks with 20 min gradients. The apolipoprotein family, inflammatory markers such as C-reactive protein, gender-related proteins and more than 40 FDA approved biomarkers are reproducibly quantified (CV<20% with label-free quantification). Furthermore, we functionally interpret a 1000 protein, quantitative plasma proteome obtained by simple peptide pre-fractionation. ‘Plasma proteome profiling’ delivers an informative portrait of a person’s health state and we envision its large-scale use in biomedicine.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dr Matthias Mann

PROVIDER: MSV000080267 | MassIVE | Fri Oct 21 14:23:00 BST 2016

SECONDARY ACCESSION(S): PXD002854

REPOSITORIES: MassIVE

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Project description:Light chain amyloidosis (AL) is a life-threatening plasma cell dyscrasia manifested by irreversible damage of multiple organs caused by monoclonal immunoglobulin light chain, production of pathogenic bone marrow plasma cells (BMPCs). Although AL is featured by both misfolding of monoclonal protein and plasma cell proliferation, the functional subclones and molecular mechanism of BMPCs in AL remain elusive. Also, inter-individual heterogeneities of AL determine the chemotherapy response and organ tropism of light chains, which require well-defined molecular subtypes. To address these, we conducted single-cell RNA sequencing (scRNA-seq) of BMPCs donated by patients with AL, patients with monoclonal gammopathy of undetermined significance (MGUS), and healthy controls. Single-cell transcriptome revealed a continuity of bone marrow plasma cell (BMPC) functional subclones, delineating DNA repair, cell proliferation, immunoglobulin production, etc., with the gradient of signaling entropy and immunoglobulin production. The amyloidosis-associated genes, such as the amyloid-beta binding Apolipoprotein E (APOE), Cystatin 3 (CST3), and Complement C1q A Chain (C1QA), were up-regulated in a subclone enriched in AL. The speculated light chain-producing subclones in AL up-regulated neutrophil degranulation pathways, transport to and modifications in Golgi apparatus, and asparagine N-linked protein glycosylation. Cyclin D1 (CCND1)hi AL, consisted of larger main subclones which highly expressed Bcl-2 complex and B-cell differentiation genes, was sensitive to venetoclax that targets Bcl-2. A major subset of CCND1low AL harbored larger carbohydrate-synthesizing subclone and up-regulated CCND2 and the amyloidosis-associated genes. Collectively, our results provided frontier insights into the functional subclones and molecular mechanism of BMPCs in AL, associated with amyloidosis, light chain production and venetoclax sensitivity, as knowledge for the future research on AL pathogenesis, AL subtypes and AL-specific therapies.

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Plasma proteome profiling to assess human health and disease

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