Profiling the landscape of cysteine posttranslational modifications in brain aging and neurodegeneration

Cysteine residues occupy a unique position in the proteome: their thiolate side chain combines high nucleophilicity with redox sensitivity, making them prime targets for a diverse and ever-expanding array of post-translational modifications (PTMs). This review provides an overview of recent methodological developments for chemoselective site-specific detection and quantitation of the major cysteine PTMs-sulfenylation (RSOH), sulfinylation (RSO₂H), sulfonylation (RSO₃H), persulfidation (RSSH), S-nitrosylation (RSNO), and S-palmitoylation-emphasizing applications in brain aging and neurodegeneration. In neural tissues, these approaches have begun to map age-dependent increases in sulfenylation and sulfonylation, declines in persulfidation, and aberrant S-nitrosylation and palmitoylation linked to Alzheimer's, Parkinson's, and Huntington's disease. However, significant challenges remain. Further improvements in sensitivity, specificity, and quantitative accuracy are essential to capture low-abundance and labile modifications in complex neural tissues. These attempts should be coupled to more detailed anatomical dissection of these modifications in different parts of the brain, enabling region- and cell-type-specific insights. Advancing analytical workflows, integrating multi-dimensional data, and linking chemical modifications to biological outcomes will pave the way for innovative therapeutic strategies targeting cysteine chemistry in neurological disease.