Methionine Sulfoxide Speciation in Mouse Hippocampus Revealed by Global Proteomics Exhibits Age- and Alzheimer's Disease-Dependent Changes Targeted to Mitochondrial and Glycolytic Pathways.

Methionine oxidation to the sulfoxide form (MS ox ) is a poorly understood post-translational modification of proteins associated with non-specific chemical oxidation from reactive oxygen species (ROS), whose chemistries are linked to various disease pathologies, including neurodegeneration. Emerging evidence shows MS ox site occupancy is, in some cases, under enzymatic regulatory control, mediating cellular signaling, including phosphorylation and/or calcium signaling, and raising questions as to the speciation and functional nature of MS ox across the proteome. The 5XFAD lineage of the C57BL/6 mouse has well-defined Alzheimer's and aging states. Using this model, we analyzed age-, sex-, and disease-dependent MS ox speciation in the mouse hippocampus. In addition, we explored the chemical stability and statistical variance of oxidized peptide signals to understand the needed power for MS ox -based proteome studies. Our results identify mitochondrial and glycolytic pathway targets with increases in MS ox with age as well as neuroinflammatory targets accumulating MS ox with AD in proteome studies of the mouse hippocampus. Further, this paper establishes a foundation for reproducible and rigorous experimental MS ox -omics appropriate for novel target identification in biological discovery and for biomarker analysis in ROS and other oxidation-linked diseases.