Aging Oxidation Drives Brain Proteins Into Harmful Clumps, Study Finds

An international research team, including Martín Hugo, a lecturer in the Department of Biochemistry and Molecular Biology at the Universitat Autònoma de Barcelona (UAB), has described how two opposing chemical modifications of proteins regulate the behavior of key brain proteins during aging. The study, published in the journal Nature Structural Molecular Biology, focuses on two processes called sulfenylation and persulfidation.

The researchers found that protein oxidation accumulates with age, a process that promotes excessive condensation of proteins and the formation of aggregates. Persulfidation, a process regulated by the production of hydrogen sulfide, has the opposite effect, keeping proteins in a fluid and functional state. This balance controls a process called liquid-liquid phase separation in proteins such as synapsin 1 and G3BP2, both involved in neuronal function and the cell's stress responses.

When a cell's production of hydrogen sulfide fails, these proteins become trapped in an abnormal state, and mice in the study developed shorter lifespans and traits resembling neurodegeneration. Compounds that raise hydrogen sulfide levels, such as ergothioneine, were able to reverse this effect in cells — a finding the researchers say could open a path toward treatments for age-related brain diseases.

The team also built an interactive platform that lets users explore a complete atlas of cysteine modifications across different ages and molecular pathways, intended to help other scientists study how these oxidative changes relate to disease.