From prion diseases to prion-like propagation mechanisms of neurodegenerative diseases

Abstract

Prion diseases are fatal neurodegenerative sporadic, inherited, or acquired disorders. In humans, Creutzfeldt-Jakob disease is the most studied prion disease. In animals, the most frequent prion diseases are scrapie in sheep and goat, bovine spongiform encephalopathy in cattle, and the emerging chronic wasting disease in wild and captive deer in North America. The hallmark of prion diseases is the deposition in the brain of PrP(Sc), an abnormal β -sheet-rich form of the cellular prion protein (PrP(C)) (Prusiner 1982). According to the prion hypothesis, PrP(Sc) can trigger the autocatalytic conversion of PrP(C) into PrP(Sc), presumably in the presence of cofactors (lipids and small RNAs) that have been recently identified. In this review, we will come back to the original works that led to the discovery of prions and to the protein-only hypothesis proposed by Dr. Prusiner. We will then describe the recent reports on mammalian synthetic prions and recombinant prions that strongly support the protein-only hypothesis. The new concept of "deformed templating" regarding a new mechanism of PrP(Sc) formation and replication will be exposed. The review will end with a chapter on the prion-like propagation of other neurodegenerative disorders, such as Alzheimer's and Parkinson's disease and tauopathies.

Figure 1

Proposed mechanisms of PrP^C conversion into PrP^Sc, with exogenous (a) or genetic (b) prions. Wild-type PrP^C is represented by a cylinder colored in blue, mutated PrP^C is outlined in blue, and PrP^Sc is represented by red square.

Figure 2

Schematic representation of two possible mechanisms of de novo propagation of prions from recPrP fibrils. (a) In this model, the preparation of recPrP fibrils contains very small amounts of classical PrP^Sc. A long incubation time is required to amplify and propagate in vivo this minute amount of PrP^Sc. (b) The second model (“deformed templating" mechanism) hypothesizes that there is no classical PrP^Sc in the fibril preparation and that recPrP fibrils can be converted into PrPres (PrP^Sc-like structures) with low efficiency. After several passages, these PrP^Sc-like structures progressively adopt the structural features of classical PrP^Sc. Schema adapted from Makarava et al., 2011 [48].