The study investigates the neuroprotective function of DJ-1, a protein associated with Parkinson's disease (PD). DJ-1 is known to accumulate in acidic forms after oxidative stress, suggesting a protective role. The researchers systematically mutated cysteine residues in human DJ-1 to identify the key modification responsible for its protective effects. They found that oxidation of Cys106 to cysteine-sulfenic acid (C106-SO2H) is crucial for DJ-1's protective function. C106A mutants, which lack this modification, failed to protect against oxidative stress and mitochondrial damage. The study also revealed that DJ-1 localizes to mitochondria after oxidative stress, and this localization is blocked in C106A mutants. These findings suggest that DJ-1's neuroprotective function is mediated by the oxidation of C106, which triggers mitochondrial localization and protection against cell death. The results provide insights into the molecular mechanisms underlying DJ-1's role in PD and its potential therapeutic targets.The study investigates the neuroprotective function of DJ-1, a protein associated with Parkinson's disease (PD). DJ-1 is known to accumulate in acidic forms after oxidative stress, suggesting a protective role. The researchers systematically mutated cysteine residues in human DJ-1 to identify the key modification responsible for its protective effects. They found that oxidation of Cys106 to cysteine-sulfenic acid (C106-SO2H) is crucial for DJ-1's protective function. C106A mutants, which lack this modification, failed to protect against oxidative stress and mitochondrial damage. The study also revealed that DJ-1 localizes to mitochondria after oxidative stress, and this localization is blocked in C106A mutants. These findings suggest that DJ-1's neuroprotective function is mediated by the oxidation of C106, which triggers mitochondrial localization and protection against cell death. The results provide insights into the molecular mechanisms underlying DJ-1's role in PD and its potential therapeutic targets.