Prion (proteinaceous infectious particle) diseases

The prion protein (PrP) is the causative agent of transmissible spongiform encephalopathies (TSE), including Creutzfeldt-Jakob disease in humans, scrapie in sheep, and bovine spongiform encephalopathy in cattle (popularly called “mad cow” disease). After an extensive series of purification procedures, scientists were surprised to find that the infectivity of the agent causing scrapie in sheep was associated with a single protein species that was not complexed with detectable nucleic acid. This infectious protein is designated PrP^Sc (Sc = scrapie). It is highly resistant to proteolytic degradation and tends to form insoluble aggregates of fibrils, similar to the amyloid found in some other diseases of the brain. A noninfectious form of PrP^C (C = cellular), encoded by the same gene as the infectious agent, is present in normal mammalian brains on the surface of neurons and glial cells. Thus, PrP^C is a host protein. No primary structure differences or alternate posttranslational modifications have been found between the normal and the infectious forms of the protein. The key to becoming infectious apparently lies in changes in the three-dimensional conformation of PrP^C. Research has demonstrated that a number of α-helices present in noninfectious PrP^C are replaced by β-sheets in the infectious form (Fig. 1). This conformational difference is presumably what confers relative resistance to proteolytic degradation of infectious prions and permits them to be distinguished from the normal PrP^C in infected tissue. The infective agent is, thus, an altered version of a normal protein, which acts as a template for converting the normal protein to the pathogenic conformation. The TSE are invariably fatal, and no treatment is currently available that can alter this outcome.

Figure 1: One proposed mechanism for multiplication of infectious prions. PrP= prion protein; PrP^c = prion protein cellular; PrP^Sc = prion protein scrapie.