Protein thiol alterations drive pathologic liquid–liquid phase separation in the aging brain
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.
Authors
- Dunja Petrovic
- Bindu D. Paul (ORCID: https://orcid.org/0000-0002-1862-6103)
- Davide D’Andrea
- Christian Münch (ORCID: https://orcid.org/0000-0003-3832-090X)
- Erik Lacko (ORCID: https://orcid.org/0009-0001-7797-6509)
- Miloš R. Filipović (ORCID: https://orcid.org/0000-0003-0060-0041)
- Albert Sickmann (ORCID: https://orcid.org/0000-0002-2388-5265)
- Dragomir Milovanović (ORCID: https://orcid.org/0000-0002-6625-1879)
- Jordan L. Morris (ORCID: https://orcid.org/0000-0002-4663-4776)
- Antonia Katsouda (ORCID: https://orcid.org/0000-0002-3253-2250)
- Ferran Comas (ORCID: https://orcid.org/0000-0003-1801-3291)
- Ilan Davis (ORCID: https://orcid.org/0000-0002-5385-3053)
- Christian Hoffmann (ORCID: https://orcid.org/0000-0003-3478-2410)
- Suyuan Chen (ORCID: https://orcid.org/0000-0003-0972-936X)
- Sunil Jamuna Tripathi (ORCID: https://orcid.org/0000-0001-9107-2437)
- Vladimir Jovanović (ORCID: https://orcid.org/0000-0002-8056-5065)
- Julien Prudent (ORCID: https://orcid.org/0000-0003-3821-6088)
- Michael P. Murphy (ORCID: https://orcid.org/0000-0003-1115-9618)
- Thibaut Vignane (ORCID: https://orcid.org/0000-0002-3377-3187)
- Jan Lj. Miljković (ORCID: https://orcid.org/0000-0002-1910-9677)
- Kostas Tokatlidis (ORCID: https://orcid.org/0000-0001-6295-8183)
- Andrew A. Pieper (ORCID: https://orcid.org/0000-0001-6299-6577)
- Andreas Papapetropoulos (ORCID: https://orcid.org/0000-0002-4253-5930)
- Natalija Polović (ORCID: https://orcid.org/0000-0002-9127-2014)
- Polina Reichert (ORCID: https://orcid.org/0000-0001-6239-7646)
- Edwin Vázquez‐Rosa (ORCID: https://orcid.org/0009-0005-4508-5217)
- Martín Hugo (ORCID: https://orcid.org/0000-0003-3430-6457)
- H. Wang (ORCID: https://orcid.org/0009-0000-5517-3038)
- Suvagata Roy Chowdhury (ORCID: https://orcid.org/0000-0001-6127-5276)
- Marko Miler
- Suwarna Chakraborty
- Danail Stoychev
- Johannes V. Tromm
Institutions
- Goethe University Frankfurt (DE)
- Universitat Autònoma de Barcelona (ES)
- Johns Hopkins University (US)
- National and Kapodistrian University of Athens (GR)
- Academy of Athens (GR)
- University of Cambridge (GB)
- Johns Hopkins Medicine (US)
- Humboldt-Universität zu Berlin (DE)
- University of Belgrade (RS)
- Biomedical Research Foundation of the Academy of Athens (GR)
- University Hospitals Cleveland Medical Center (US)
- Geriatric Research Education and Clinical Center (US)
- Louis Stokes Cleveland VA Medical Center (US)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Lieber Institute for Brain Development (US)
- University School (US)
- Case Western Reserve University (US)
- Freie Universität Berlin (DE)
- University of Glasgow (GB)
- MRC Mitochondrial Biology Unit (GB)
- City of Glasgow College (GB)
Publication Details
- Journal
- Nature Structural & Molecular Biology
- Published
- 2026-07-30
- DOI
- https://doi.org/10.1038/s41594-026-01857-w
- Primary Topic
- Sulfur Compounds in Biology
- Type
- article
- Field-Weighted Citation Impact
- 0.00