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 PrPSc, an abnormal β-sheet-rich form of the cellular prion protein (PrPC) (Prusiner 1982). According to the prion hypothesis, PrPSc can trigger the autocatalytic conversion of PrPC into PrPSc, 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 PrPSc 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. 1. The Story of the Prion Protein That Was Mistaken for a Virus Prion diseases and prion infectious agents [1] are among the most fascinating biological topics of the twentieth century and have been under the spotlight for the last 30 years, particularly due to the striking epidemic of bovine spongiform encephalopathy (BSE), which started in Great Britain in the mid-eighties and then spread to other European countries [2]. The transmission of the bovine prion agent to humans, possibly through consumption of prion-contaminated beef products, led to the emergence of a new human prion disease, named “variant” Creutzfeldt-Jakob disease (vCJD), in young people [3]. Recently, several cases of secondary human-to-human transmission of vCJD through transfusion of prion-contaminated blood [4–6] have raised doubts within the scientific community about the safety of blood products and highlighted the crucial need of diagnostic tests for prion detection in blood. Currently, the development of reliable blood tests and of therapies is the main mission of scientists working in the prion field. Historically, the infectious agent that causes prion diseases was supposed to be an atypical virus belonging to the category of “slow viruses” [7, 8]. Then, in 1967, Pattison and colleagues reported [9]
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