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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月30日

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  • Thibaut Vignane,
  • Martín Hugo,
  • Christian Hoffmann,
  • Polina Reichert,
  • Antonia Katsouda,
  • Davide D’Andrea,
  • Han Wang,
  • Johannes V. Tromm,
  • Marko Miler,
  • Ferran Comas,
  • Dunja Petrovic,
  • Suyuan Chen,
  • Jan Lj. Miljkovic,
  • Danail Stoychev,
  • Erik Lacko,
  • Vladimir M. Jovanovic,
  • Suwarna Chakraborty,
  • Sunil J. Tripathi,
  • Edwin Vázquez-Rosa,
  • Jordan L. Morris,
  • Suvagata Roy Chowdhury,
  • Julien Prudent,
  • Albert Sickmann,
  • Natalija Polovic,
  • Andrew A. Pieper,
  • Ilan Davis,
  • Kostas Tokatlidis,
  • Bindu D. Paul,
  • Michael P. Murphy,
  • Christian Münch,
  • Andreas Papapetropoulos,
  • Dragomir Milovanovic,
  • Milos R. Filipovic

摘要

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.