Aging Oxidation Drives Brain Proteins into Harmful Condensates

A team of international researchers, led in part by Martín Hugo, a Serra Húner lecturer in the Department of Biochemistry and Molecular Biology at the University of Barcelona (UAB), has published new findings on how two opposing chemical modifications of proteins—sulfenylation and persulfidation—control the activity of key brain proteins during the aging process. The study, appearing in *Nature Structural & Molecular Biology*, demonstrates that these redox-based post‑translational changes can either activate or inhibit protein functions that are critical for neuronal health.

The authors used a combination of mass spectrometry, structural biology and functional assays to map the dynamic interplay between sulfenylation and persulfidation on a panel of proteins involved in synaptic signaling, mitochondrial regulation and oxidative stress response. Their data reveal that aging shifts the balance toward increased sulfenylation, which in turn dampens protective pathways, while persulfidation acts as a counteracting mechanism that preserves protein integrity. By pinpointing specific cysteine residues that undergo these modifications, the study provides a mechanistic framework for understanding how redox dysregulation contributes to age‑related neurodegeneration.

These insights open new avenues for therapeutic strategies aimed at restoring the redox equilibrium in the aging brain. Targeting the enzymes that mediate sulfenylation and persulfidation could potentially enhance neuronal resilience and slow the progression of neurodegenerative disorders. The research underscores the importance of post‑translational modifications in brain aging and highlights the value of interdisciplinary collaboration in uncovering complex molecular processes.