Prion diseases: a riddle wrapped in a mystery inside an enigma

It is now widely accepted that many structurally diverse proteins can misfold and cause so-called "conformational diseases", including the most common neurodegenerations, Alzheimer's disease and Parkinson's disease. The conversion of largely a-helical or random coil proteins into cross-beta-pleated sheet conformations that form first oligomers and then fibrils underlies these disorders. However, this alpha- to beta-structure transition seems to be a generic propensity of all globular proteins, not only those involved in neurodegenerations, not to mention "prion diseases". Metaphorically, all these neurodegenerations are "infectious" in the sense that misfolded beta-sheeted conformers are formed in a nucleation process in which preformed metastable oligomer acts as a seed (a nucleus) to convert a normal into an abnormal protein. However, in none but transmissible spongiform encephalopathies (TSEs) has infectivity in a microbiological sense ever been observed, and even in TSEs the formation of misfolded protein is not necessarily accompanied by the generation of infectivity de novo. Furthermore, certain "prion diseases" are not TSEs but just "proteinopathies" caused by accumulation of abnormally misfolded PrPd. The presence of a massive amount of PrP-amyloid and no infectivity casts doubts on whether TSEs are really infectious amyloidoses. The misfolding of PrP may yet prove to be an epiphenomenon secondary to infection with a still unknown infectious agent. If, on the other hand, the purely proteinaceous character of the replicating unit of TSE infectivity is ultimately found to be correct, the critical issues become 1) the mechanism by which a misfolded PrP template induces normal protein molecules to adopt the same pathologically misfolded conformation, and 2) the intracellular conditions that are responsible for strain differences in these molecules.