PRIONS AS AGENTS OF DISEASE (Extracted from Internal Medicine. Farreras - Rozman, 14th edition, 2000) There is a group of degenerative diseases of the human central nervous system (CNS) and of some animals that are transmissible and manifest in various clinical forms, although most have a very long incubation period. In humans, the most paradigmatic diseases of this group are kuru (which means "tremor" in the language of a tribal cannibal group in Papua New Guinea) and Creutzfeldt-Jakob disease, and in animals bovine spongiform encephalopathy ( mad cow disease) and scrapie (in sheep). These diseases are not caused by any conventional pathogen, but are caused by a transmissible protein that multiplies in the host, called a "prion." A prion is defined as an infectious pathogen with a protein structure, resistant to procedures that modify or hydrolyze nucleic acids. The term was introduced by Prusiner in 1982 with the purpose of highlighting that they are agents (proteinaceous infectious particles) other than viruses and viroids. Human and other animal cells produce under physiological conditions a normal protein of high homology in all the species studied. This protein has been called PrP (prion protein). Its physiological function is unknown, but it is more abundant in CNS cells than in other tissues. In the brain tissue preparations of scrapie animals, a protein with different physicochemical characteristics from conventional proteins was detected, since it was resistant to proteases and other substances with proteolytic activity and capable of forming aggregates and fibrillar deposits. It had the same amino acid sequence as normal PrP, but had undergone a conformational (folding) change and was named sc PrP (sc for scrapie). Proteins with the same characteristics have been found in the rest of the degenerative communicable diseases: prions. The mechanism of production of sc PrP and the precise way of exerting its pathogenic action are unknown, although it is known that, unlike the normal form, it accumulates inside cells and is precipitated outside as amyloid or fibrils. . Once the change in one or a few molecules of normal PrP has occurred, the modified form PrP sc would act on the normal protein molecules of the cell and catalyze their transformation to the altered form. The propagation would act through a domino effect, whereby an infectious molecule attacks a normal one, turns it into an abnormal one and this one attacks another normal one, and so on. Prions are transmitted horizontally in nature through the ingestion of meat or offal, particularly brain, and also by other unknown mechanisms. The epizootic described for the first time in 1986 in the United Kingdom would have been transmitted to cattle through feed made with meat and bone meal from sheep suffering from scrapie. The transmitted prions would reach the CNS through neuronal axons and catalyze the transformation of normal PrP. Prions are known to be resistant to heat, drying, and ionizing and ultraviolet radiation, as well as various chemical agents such as alcohol, acetone, ether, hydrogen peroxide, etc., being the recommended treatments for the material. Contaminated 1N sodium hydroxide for one hour or autoclaved at 134-138ºC for 2 h or, better yet, a combination of both.
Question:
How are the conformational changes of the infectious protein with respect to the normal one. Could conformational changes explain the difference in solubility and partial resistance to Pr sc proteases? Generalize how structure affects function
