| Title: |
Deep Visual Proteomics maps proteotoxicity in a genetic liver disease |
| Authors: |
Rosenberger, Florian A; Mädler, Sophia C; Thorhauge, Katrine Holtz; Steigerwald, Sophia; Fromme, Malin; Lebedev, Mikhail; Weiss, Caroline A M; Oeller, Marc; Wahle, Maria; Metousis, Andreas; Zwiebel, Maximilian; Schmacke, Niklas A; Detlefsen, Sönke; Boor, Peter; Fabián, Ondřej; Fraňková, Soňa; Krag, Aleksander; Strnad, Pavel; Mann, Matthias |
| Source: |
Rosenberger, F A, Mädler, S C, Thorhauge, K H, Steigerwald, S, Fromme, M, Lebedev, M, Weiss, C A M, Oeller, M, Wahle, M, Metousis, A, Zwiebel, M, Schmacke, N A, Detlefsen, S, Boor, P, Fabián, O, Fraňková, S, Krag, A, Strnad, P & Mann, M 2025, 'Deep Visual Proteomics maps proteotoxicity in a genetic liver disease', Nature, vol. 642, no. 8067, pp. 484-491. https://doi.org/10.1038/s41586-025-08885-4 |
| Publication Year: |
2025 |
| Collection: |
University of Southern Denmark: Research Output / Syddansk Universitet |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
0028-0836 |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/40240610; info:eu-repo/semantics/altIdentifier/pissn/0028-0836 |
| DOI: |
10.1038/s41586-025-08885-4 |
| Availability: |
https://portal.findresearcher.sdu.dk/da/publications/e2fc9224-a492-4899-a1df-abe6afdade9e; https://doi.org/10.1038/s41586-025-08885-4; https://findresearcher.sdu.dk/ws/files/291173915/s41586-025-08885-4.pdf |
| Rights: |
info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.1335E10A |
| Database: |
BASE |