Protein thiol alterations drive pathologic liquid–liquid phase separation in the aging brain
Vignane et al. show that age-related protein oxidation disrupts normal brain protein organization, promoting harmful condensates and aggregation linked to neurodegeneration, whereas hydrogen sulfide-driven persulfidation
Aging disrupts cellular homeostasis by altering the regulation of protein post-translational modifications (PTMs) and biomolecular condensation. The mouse brain was studied using chemoproteomic techniques to generate an atlas of cysteine PTMs, revealing that age-related increases in thiol oxidation promote the formation of harmful biomolecular condensates. In contrast, protein persulfidation, regulated by hydrogen sulfide production, inhibits biomolecular condensation and preserves protein function. The phase separation properties of synapsin 1 and G3BP2 were influenced by age-induced alterations in cysteine PTMs, leading to impaired neurotransmitter release and defective stress granule formation and resolution. Mice deficient in cystathionine γ-lyase, the enzyme responsible for hydrogen sulfide production, exhibited reduced lifespans and spontaneously developed protein aggregates with age. The findings suggest that targeting protein persulfidation may mitigate age-related diseases.