Cysteine oxidation in the brains of old mice alters protein assembly into droplets
Cysteine oxidation in the brains of old mice alters protein assembly into droplets
In a paper published on July 30, the authors examined how age affects chemical modifications of cysteine, an amino acid found in many proteins. In mice, this shift altered the behavior of synapsin-1 and G3BP2, while the hydrogen sulfide donor H₂S accelerated stress granule disassembly in cells.
Proteins inside cells continually gather into small, temporary clusters and then disperse. This process allows nerve terminals to maintain a reserve of neurotransmitter vesicles and helps cells endure oxidative stress. This reversible assembly of proteins into droplets is called phase separation.
The authors compared the frontotemporal brain region of mice at 10 weeks, 10 months, and 18 months of age. They measured two chemical states of cysteine: sulfenylation, in which oxygen is added, and persulfidation, in which a sulfur atom is added. Sulfenylation increased with age, while persulfidation decreased. An analysis of total protein abundance showed that this shift could not be explained by changes in the amounts of the proteins themselves.
The enzyme CSE produces H₂S and maintains persulfidation. In 10-week-old mice with the Cse gene knocked out, the pattern of cysteine oxidation already resembled that of 18-month-old animals. Genetic loss of CSE therefore shifted the chemical state of cysteine in the same direction as aging did in ordinary mice.
The team examined the consequences for two proteins. Synapsin-1 organizes the reserve pool of neurotransmitter vesicles. Its oxidation altered the properties of condensates and was associated with signal release in primary mouse neurons. G3BP2 assembles stress granules, which are temporary complexes of RNA and proteins. In CSE-deficient cells, these granules persisted longer after stress.
In a purified system, H₂S dissolved preassembled G3BP2 condensates. In striatal cells, the slow-releasing H₂S donor GYY4137 accelerated granule disassembly after oxidative stress. The authors observed the same effect in fibroblasts from a 79-year-old donor.