Organic Chemistry in Neurodegenerative Disorders - Physical Organic Chemistry and Bioorganic Free Radical Chemistry of Prion Protein

The central event in prion diseases(including mad cow disease) is the structural transformation of a single protein, i. e., prion protein, from its benign form to its diseased and infectious form. Protein-only hypothesis as an evolutionary model for viral replication has been tested in a rigorous way in prion research. In the diseases, the spontaneous and irreversible protein structural transformation was completed within a few months, the uniformly generated infectious prions displays an extraordinary resistance to inactivation, and exhibits a high ability to infect animals, suggesting that a vital energy source is required for the production of infectious prions. Considering the high oxygen-respiration rate in the brains of mammals, oxidative damage to prion protein can be the crucial factor. Both theoretical consideration of the nature of protein radical reactions and a large body of previously unraveled feature of scrapie and prion diseases have provided multiple distinct lines of compelling evidence, persuasively supporting a conclusion that the infectious agents are prion(free) radicals produced from protein oxidative damage. To facilitate a better understanding of the prion chemistry, in this multidisciplinary review, clinical, physiological, immunological and biochemical aspects of the diseases are provided to demonstrate for the frist time that diseased(infectious, scrapie) prions are very likely formed from prion radical-mediated oxidative damage to prion proteins.