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Protein thiol alterations drive pathologic liquid-liquid phase separation in the aging brain.

Overview

Authors: Thibaut Vignane1,2, Martín Hugo1,3, Christian Hoffmann4, Polina Reichert5, Antonia Katsouda6,7, Davide D’Andrea5, Han Wang4, Johannes V Tromm4, Marko Miler1, Ferran Comas1, Dunja Petrovic1, Suyuan Chen1, Jan Lj Miljkovic8, Danail Stoychev5, Erik Lacko5, Vladimir M Jovanovic9, Suwarna Chakraborty10, Sunil J Tripathi10, Edwin Vázquez-Rosa11,12,13,14, Jordan L Morris8
and 13 other authorsSuvagata Roy Chowdhury8, Julien Prudent8, Albert Sickmann1, Natalija Polovic15, Andrew A Pieper11,12,13,14,16,17, Ilan Davis5, Kostas Tokatlidis5, Bindu D Paul10,18,19,20, Michael P Murphy8,21, Christian Münch2, Andreas Papapetropoulos6,7, Dragomir Milovanovic4, Milos R Filipovic1,5
ORCID iDs: Thibaut Vignane, Martín Hugo, Christian Hoffmann, Han Wang, Johannes V Tromm, Marko Miler, Jan Lj Miljkovic, Vladimir M Jovanovic, Sunil J Tripathi, Edwin Vázquez-Rosa, Julien Prudent, Albert Sickmann, Natalija Polovic, Andrew A Pieper, Bindu D Paul, Michael P Murphy, Christian Münch, Andreas Papapetropoulos, Dragomir Milovanovic, Milos R Filipovic
21 affiliations
  1. Leibniz Institute for Analytical Sciences, ISAS, e.V., Dortmund, Germany
  2. Institute of Molecular Systems Medicine, Faculty of Medicine, Goethe University, Frankfurt, Germany
  3. Present Address: Serra Húnter Fellow, Departament de Bioquimica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
  4. Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, Germany
  5. School of Molecular Biosciences, MVLS College, University of Glasgow, Glasgow, UK
  6. Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
  7. Laboratory of Pharmacology, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
  8. MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
  9. Bioinformatics Solution Center, Institute for Informatics, Freie Universität Berlin, Berlin, Germany
  10. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD USA
  11. Department of Psychiatry, Case Western Reserve University, Cleveland, OH USA
  12. Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH USA
  13. Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH USA
  14. Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH USA
  15. Department of Biochemistry, Faculty of Chemistry, University of Belgrade, Belgrade, Serbia
  16. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH USA
  17. Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH USA
  18. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD USA
  19. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD USA
  20. Lieber Institute for Brain Development, Baltimore, MD USA
  21. Department of Medicine, University of Cambridge, Cambridge, UK
Institutions: Goethe University Frankfurt (Germany); Leibniz Institute for Analytical Sciences - ISAS (Germany); Universitat Autònoma de Barcelona (Spain); Humboldt-Universität zu Berlin (Germany); Berlin Institute of Health at Charité - Universitätsmedizin Berlin (Germany); Freie Universität Berlin (Germany); Charité - Universitätsmedizin Berlin (Germany); University of Glasgow (United Kingdom); National and Kapodistrian University of Athens (Greece); Biomedical Research Foundation of the Academy of Athens (Greece); University of Cambridge (United Kingdom); MRC Mitochondrial Biology Unit (United Kingdom); Johns Hopkins University (United States); University Hospitals of Cleveland (United States); University Hospitals Cleveland Medical Center (United States); Louis Stokes Cleveland VA Medical Center (United States); Case Western Reserve University (United States); University of Belgrade (Serbia); Johns Hopkins Medicine (United States); Lieber Institute for Brain Development (United States)
Journal: Nature structural & molecular biology, volume 33, issue 8, pages 1252-1265
Dates: received 14 May 2025; accepted 2 July 2026; published online 30 July 2026; in print 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41594-026-01857-w · PMID 42533105 · PMCID PMC13468144 · OpenAlex W7171770306
Open access: hybrid, a free copy (OpenAlex)
Status: empty repository
Categories: genetics / omics (modality), mouse (organism), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics, Evoked potentials
Keywords: Proteomics, Post-translational modifications
MeSH: Aging*, Brain*, Sulfhydryl Compounds*, Animals, Biomolecular Condensates, Cystathionine gamma-Lyase, Cysteine, Hydrogen Sulfide, Mice, Neurodegenerative Diseases, Oxidation-Reduction, Phase Separation, Protein Processing, Post-Translational, Stress Granules (* major topic)
Topic: Sulfur Compounds in Biology (Biochemistry, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Wellcome Trust (220257/Z/20/Z)
Citations: cited by 1 paper (Europe PMC); 98 references in the paper

Abstract

Cellular homeostasis relies on regulation of processes, including protein post-translational modifications (PTMs) and biomolecular condensation. Aging disrupts the equilibrium of these processes, increasing susceptibility to disease and mortality. Here we used chemoproteomic techniques to generate an atlas of cysteine PTMs in the mouse brain and showed that age-related increases in thiol oxidation promoted the formation of biomolecular condensates. By contrast, protein persulfidation, regulated by hydrogen sulfide production, inhibited biomolecular condensation, preserving protein function. Age-induced alterations in cysteine PTMs influenced the phase separation properties of synapsin 1 and G3BP2, leading to impaired neurotransmitter release and defective stress granule formation and resolution, features associated with aging and neurodegenerative diseases. Mice deficient in cystathionine γ-lyase, the enzyme responsible for hydrogen sulfide production, exhibited reduced lifespans and spontaneously developed protein aggregates with age. Our results highlight the therapeutic potential of protein persulfidation in reversal of dysregulated biomolecular condensation and suggest that sulfide donors could be used to mitigate age-related diseases.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

figshare 32817593

License: CC-BY-4.0
State: the link answers, verified on 27 September 2026
Evidence: files inventoried
Size: 3 files, 0 scripts
Software Heritage: not checked
Found in: the references
Not found: README, license file, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 27 September 2026: the link answers (HTTP 200)
  • 27 September 2026: the link answers (HTTP 200)
At the source:

The paper's code and data availability statement is in the Data section.

Tracing map

Proposed by the machine: these links were found in the paper and verified at the source, without human review. The map will receive a Zenodo DOI once one of the paper's authors has validated it with their ORCID.

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  • 1 repository of the authors' code, each at its verified commit, with its license and how the link was found in the paper;
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Data

Datasets cited

Data availability

Data and materials can be obtained from the corresponding authors upon request. All proteomic data are available through PRIDE97 under accession codes PXD045785 (http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD045785) (sulfenylome and total proteome); PXD045806 (http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD045806) (persulfidation and sulfonylation); and PXD045820 (http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD045820) (TPP of WT and Cse−/− MEFs upon H2O2 stress). Gallyas silver staining images of sections from 18-month-old WT and Cse−/− mice are available via BioImage Archive98 (10.6019/S-BIAD1604). Pathological phospho-tau tangle and amyloid-β deposit formation in WT and CSE-deficient mouse brain are available via Figshare at 10.6084/m9.figshare.32817593(ref. 65). An online platform for interactive data exploration is available at https://www.agingredox.org/. Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Publisher: — → Nature Portfolio

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 33 authors, 2 keywords, 14 MeSH terms, 1 funder, 98 references.

Cite

This paper

Vignane, T., Hugo, M., Hoffmann, C., Reichert, P., Katsouda, A., D’Andrea, D., Wang, H., Tromm, J. V., Miler, M., Comas, F., Petrovic, D., Chen, S., Miljkovic, J. L., Stoychev, D., Lacko, E., Jovanovic, V. M., Chakraborty, S., Tripathi, S. J., Vázquez-Rosa, E., . . . Filipovic, M. R. (2026). Protein thiol alterations drive pathologic liquid-liquid phase separation in the aging brain. Nature structural & molecular biology, 33(8), 1252-1265. https://doi.org/10.1038/s41594-026-01857-w

BibTeX

@article{vignane2026protein,
author = {Vignane, Thibaut and Hugo, Martín and Hoffmann, Christian and Reichert, Polina and Katsouda, Antonia and D’Andrea, Davide and Wang, Han and Tromm, Johannes V and Miler, Marko and Comas, Ferran and Petrovic, Dunja and Chen, Suyuan and Miljkovic, Jan Lj and Stoychev, Danail and Lacko, Erik and Jovanovic, Vladimir M and Chakraborty, Suwarna and Tripathi, Sunil J and Vázquez-Rosa, Edwin and Morris, Jordan L and Chowdhury, Suvagata Roy and Prudent, Julien and Sickmann, Albert and Polovic, Natalija and Pieper, Andrew A and Davis, Ilan and Tokatlidis, Kostas and Paul, Bindu D and Murphy, Michael P and Münch, Christian and Papapetropoulos, Andreas and Milovanovic, Dragomir and Filipovic, Milos R},
title = {{Protein thiol alterations drive pathologic liquid-liquid phase separation in the aging brain}},
journal = {Nature structural \& molecular biology},
year = {2026},
month = jul,
volume = {33},
number = {8},
pages = {1252--1265},
publisher = {Nature Portfolio},
issn = {1545-9993},
doi = {10.1038/s41594-026-01857-w},
url = {https://doi.org/10.1038/s41594-026-01857-w},
pmid = {42533105},
pmcid = {PMC13468144}
}

RIS

TY - JOUR
AU - Vignane, Thibaut
AU - Hugo, Martín
AU - Hoffmann, Christian
AU - Reichert, Polina
AU - Katsouda, Antonia
AU - D’Andrea, Davide
AU - Wang, Han
AU - Tromm, Johannes V
AU - Miler, Marko
AU - Comas, Ferran
AU - Petrovic, Dunja
AU - Chen, Suyuan
AU - Miljkovic, Jan Lj
AU - Stoychev, Danail
AU - Lacko, Erik
AU - Jovanovic, Vladimir M
AU - Chakraborty, Suwarna
AU - Tripathi, Sunil J
AU - Vázquez-Rosa, Edwin
AU - Morris, Jordan L
AU - Chowdhury, Suvagata Roy
AU - Prudent, Julien
AU - Sickmann, Albert
AU - Polovic, Natalija
AU - Pieper, Andrew A
AU - Davis, Ilan
AU - Tokatlidis, Kostas
AU - Paul, Bindu D
AU - Murphy, Michael P
AU - Münch, Christian
AU - Papapetropoulos, Andreas
AU - Milovanovic, Dragomir
AU - Filipovic, Milos R
TI - Protein thiol alterations drive pathologic liquid-liquid phase separation in the aging brain
T2 - Nature structural & molecular biology
J2 - Nat Struct Mol Biol
PY - 2026
DA - 2026/07/30
VL - 33
IS - 8
SP - 1252
EP - 1265
SN - 1545-9993
PB - Nature Portfolio
DO - 10.1038/s41594-026-01857-w
UR - https://doi.org/10.1038/s41594-026-01857-w
LA - en
ER -

CSL-JSON

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