Uncovering Neurodegenerative Protein Modifications via Proteomic Profiling

Degenerative protein modifications (DPMs) are caused by nonenzymatic chemical reactions that induce changes in protein structure and function which promote disease initiation, pathological progression and also natural aging. These undesirable DPMs include oxidation, carbonylation, carbamylation, glycation, deamidation, isomerization, nitration, and racemization, which impart deleterious structural and functional changes on extracellular matrix proteins and long-lived cell types such as cardiomyocytes and neurons, leading to impaired overall organ function. Despite the obvious clinical importance of understanding DPM biology, the molecular mechanisms that mediate these modifications remain poorly understood largely due to the technical challenges associated with their study. However, recent advances in mass spectrometry-based proteomics technologies now permit global quantitative proteomic profiling of cell lines, animal models, and human clinical samples from a variety of different patient types. These new methods have not only uncovered changes in global protein expression levels but have also identified specific modifications of particular amino acid residues in protein backbones that are associated with disease progression. The nonenzymatic induction of DPMs as revealed by proteomic profiling can help us to better understand the underlying molecular pathology of protein dysfunction in human diseases and natural aging. This chapter discusses recent progress in understanding how proteomic profiling of patient samples derived from the central nervous system can elucidate the DPM biology of human neurodegenerative diseases.