Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

Deep Visual Proteomics maps proteotoxicity in a genetic liver disease

FA. Rosenberger, SC. Mädler, KH. Thorhauge, S. Steigerwald, M. Fromme, M. Lebedev, CAM. Weiss, M. Oeller, M. Wahle, A. Metousis, M. Zwiebel, NA. Schmacke, S. Detlefsen, P. Boor, O. Fabián, S. Fraňková, A. Krag, P. Strnad, M. Mann

. 2025 ; 642 (8067) : 484-491. [pub] 20250416

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25015477

Grant support
L40 TR001095 NCATS NIH HHS - United States

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.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc25015477
003      
CZ-PrNML
005      
20250731091016.0
007      
ta
008      
250708s2025 enk f 000 0|eng||
009      
AR
024    7_
$a 10.1038/s41586-025-08885-4 $2 doi
035    __
$a (PubMed)40240610
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a enk
100    1_
$a Rosenberger, Florian A $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany. rosenberger@biochem.mpg.de $1 https://orcid.org/0000000346046170
245    10
$a Deep Visual Proteomics maps proteotoxicity in a genetic liver disease / $c FA. Rosenberger, SC. Mädler, KH. Thorhauge, S. Steigerwald, M. Fromme, M. Lebedev, CAM. Weiss, M. Oeller, M. Wahle, A. Metousis, M. Zwiebel, NA. Schmacke, S. Detlefsen, P. Boor, O. Fabián, S. Fraňková, A. Krag, P. Strnad, M. Mann
520    9_
$a 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.
650    _2
$a lidé $7 D006801
650    12
$a proteomika $x metody $7 D040901
650    _2
$a analýza jednotlivých buněk $7 D059010
650    _2
$a hepatocyty $x metabolismus $x patologie $7 D022781
650    _2
$a játra $x patologie $x metabolismus $7 D008099
650    12
$a deficit alfa1-antitrypsinu $x patologie $x metabolismus $x genetika $7 D019896
650    _2
$a alfa-1-antitrypsin $x metabolismus $7 D000515
650    12
$a proteom $x analýza $x metabolismus $7 D020543
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a strojové učení $7 D000069550
650    _2
$a signální dráha UPR $7 D056811
650    _2
$a progrese nemoci $7 D018450
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a fenotyp $7 D010641
650    _2
$a jaterní cirhóza $x patologie $x metabolismus $7 D008103
655    _2
$a časopisecké články $7 D016428
700    1_
$a Mädler, Sophia C $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany $1 https://orcid.org/0000000178174180
700    1_
$a Thorhauge, Katrine Holtz $u Department of Gastroenterology and Hepatology, Centre for Liver Research, Odense, Denmark $u Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark $1 https://orcid.org/0000000304110373
700    1_
$a Steigerwald, Sophia $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
700    1_
$a Fromme, Malin $u 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 $1 https://orcid.org/0000000303825705
700    1_
$a Lebedev, Mikhail $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany $1 https://orcid.org/0009000836467899
700    1_
$a Weiss, Caroline A M $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
700    1_
$a Oeller, Marc $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany $1 https://orcid.org/0000000305975950
700    1_
$a Wahle, Maria $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany $1 https://orcid.org/0000000320794402
700    1_
$a Metousis, Andreas $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany $1 https://orcid.org/0000000210436591
700    1_
$a Zwiebel, Maximilian $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany $1 https://orcid.org/0000000270055619
700    1_
$a Schmacke, Niklas A $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany $u Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany $1 https://orcid.org/0000000239981139
700    1_
$a Detlefsen, Sönke $u Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark $u Department of Pathology, Odense University Hospital, Odense, Denmark $1 https://orcid.org/0000000294662333
700    1_
$a Boor, Peter $u Institute of Pathology, University Hospital Aachen RWTH, Aachen University, Aachen, Germany $1 https://orcid.org/0000000199214284 $7 xx0323557
700    1_
$a Fabián, Ondřej $u Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic $u Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic
700    1_
$a Fraňková, Soňa $u Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
700    1_
$a Krag, Aleksander $u Department of Gastroenterology and Hepatology, Centre for Liver Research, Odense, Denmark $u Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark $u Danish Institute of Advanced Study (DIAS), University of Southern Denmark, Odense, Denmark $1 https://orcid.org/0000000295984932
700    1_
$a Strnad, Pavel $u 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
700    1_
$a Mann, Matthias $u Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany. mmann@biochem.mpg.de $u NNF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. mmann@biochem.mpg.de $1 https://orcid.org/0000000312924799
773    0_
$w MED00003455 $t Nature $x 1476-4687 $g Roč. 642, č. 8067 (2025), s. 484-491
856    41
$u https://pubmed.ncbi.nlm.nih.gov/40240610 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20250708 $b ABA008
991    __
$a 20250731091010 $b ABA008
999    __
$a ok $b bmc $g 2366361 $s 1252602
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2025 $b 642 $c 8067 $d 484-491 $e 20250416 $i 1476-4687 $m Nature $n Nature $x MED00003455
GRA    __
$a L40 TR001095 $p NCATS NIH HHS $2 United States
LZP    __
$a Pubmed-20250708

Find record

Citation metrics

Archiving options