Deep Visual Proteomics maps proteotoxicity in a genetic liver disease
Nature, vol. 642, pp. 484–491
Abstract
Abstract Protein misfolding diseases, including α1-antitrypsin deficiency (AATD), pose substantial health challenges, with their cellular progression still poorly understood1–3. We use spatial proteomics by mass spectrometry and machine learning to map AATD in human liver tissue. Combining Deep Visual Proteomics (DVP) with single-cell analysis4,5, we probe intact patient biopsies to resolve molecular events during hepatocyte stress in pseudotime across fibrosis stages. We achieve proteome depth of up to 4,300 proteins from one-third of a single cell in formalin-fixed, paraffin-embedded tissue. This dataset reveals a potentially clinically actionable peroxisomal upregulation that precedes the canonical unfolded protein response. Our single-cell proteomics data show α1-antitrypsin accumulation is largely cell-intrinsic, with minimal stress propagation between hepatocytes. We integrated proteomic data with artificial intelligence-guided image-based phenotyping across several disease stages, revealing a late-stage hepatocyte phenotype characterized by globular protein aggregates and distinct proteomic signatures, notably including elevated TNFSF10 (also known as TRAIL) amounts. This phenotype may represent a critical disease progression stage. Our study offers new insights into AATD pathogenesis and introduces a powerful methodology for high-resolution, in situ proteomic analysis of complex tissues. This approach holds potential to unravel molecular mechanisms in various protein misfolding disorders, setting a new standard for understanding disease progression at the single-cell level in human tissue.
Authors 19
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Florian A. Rosenberger corresponding
Max Planck Institute of Biochemistry
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany. rosenberger@biochem.mpg.de
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Max Planck Institute of Biochemistry
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
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University of Southern Denmark
Affiliation as printed
Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
Department of Gastroenterology and Hepatology, Centre for Liver Research, Odense, Denmark
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Max Planck Institute of Biochemistry
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH, AachenHealth Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
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Max Planck Institute of Biochemistry
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
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Max Planck Institute of Biochemistry
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
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Max Planck Institute of Biochemistry
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
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Max Planck Institute of Biochemistry
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
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Max Planck Institute of Biochemistry
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
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Max Planck Institute of Biochemistry
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
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Max Planck Institute of Biochemistry · Ludwig-Maximilians-Universität München
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
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University of Southern Denmark · Odense University Hospital
Affiliation as printed
Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
Department of Pathology, Odense University Hospital, Odense, Denmark
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Pathology, University Hospital Aachen RWTH, Aachen University, Aachen, Germany
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Charles University · Institute of Clinical and Experimental Medicine · Thomayer University Hospital
Affiliation as printed
Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic
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Institute of Clinical and Experimental Medicine
Affiliation as printed
Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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University of Southern Denmark
Affiliation as printed
Danish Institute of Advanced Study (DIAS), University of Southern Denmark, Odense, Denmark
Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
Department of Gastroenterology and Hepatology, Centre for Liver Research, Odense, Denmark
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH, AachenHealth Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
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Matthias Mann corresponding
University of Copenhagen · Max Planck Institute of Biochemistry
Affiliation as printed
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany. mmann@biochem.mpg.de
NNF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. mmann@biochem.mpg.de
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