Canadian Association of Neurosciences Review: Prion Protein and Prion Diseases: The Good and the Bad

Abstract

In the 1700's a strange new disease affecting sheep was recognized in Europe. The disease later became known as “Scrapie” and was the first of a family of similar diseases affecting a number of species that are now known as the Transmissible Spongiform Encephalopathies (TSEs). The appearance of a new disease in humans linked to the consumption of meat products from infected cattle has stimulated widespread public concern and scientific interest in the prion protein and related diseases. Nearly 300 years after the first report, these diseases still merit the descriptor “strange”. This family of diseases is characterized by a unique profile of histological changes, can be transmitted as inherited or acquired diseases, as well as apparent sporadic spontaneous generation of the disease. These diseases are believed by many, to be caused by a unique protein only infectious agent. The “prion protein” (PrPC), a term first coined by Stanley Prusiner in 1982 is crucial to the development of these diseases, apparently by acting as a substrate for an abnormal disease associated form. However, aside from being critical to the pathogenesis of the disease, the function of PrPC, which is expressed in all mammals, has defied definitive description. Several roles have been proposed on the basis ofin vitrostudies, however, thus far,in vivoconfirmation has not been forthcoming. The biological features of PrPCalso seem to be unusual. Numerous mouse models have been generated in an attempt to understand the pathogenesis of these diseases. This review summarizes the current state of histological features, the etiologic agent, the normal metabolism and the function of the prion protein, as well as the limitations of the mouse models.

Wrecked regulation of intrinsically disordered proteins in diseases: pathogenicity of deregulated regulators

“…Prion diseases are characterized by the conversion of a soluble form of the glycoprotein prion protein (PrP C ) to the abnormal (infectious) scrapie form (PrP Sc ) (Gains and LeBlanc, 2007 ). NMR analysis revealed that human PrP C is a hybrid protein that contains a C-terminal globular domain extending from residues 125–228, and an N-terminal disordered tail (Zahn et al, 2000 ).…”

Redox Control of Prion and Disease Pathogenesis

“…Cross-linking of PrP C on the plasma membrane has been noted to induce neurotoxicity (209), perhaps by activating certain apoptotic pathways or by compromising the normal function of PrP C (174,(182)(183)(184). A compelling set of observations suggest that subversion or loss of normal function of PrP C is an equally significant cause of prion disease-associated neurotoxicity (34,66,79,155). The specific function of PrP C involved in this process, however, has been difficult to identify because of the variety of functional activities attributed to this protein, based on the experimental design and the method used.…”

Demonstration of a protein with enhanced resistance to proteinase K in transmissible cytopathic condition elicited by cell-free lysate of free-living ameba Naegleria gruberi

“…It is well established that some proteins are capable of turning into infectious agents and cause diseases in both mammals and fungi [1,2]. These proteinaceous pathogens are called prions after Stanley B. Prusiner's landmark discovery published in 1982 [3].…”