History of Prions and transmission of protein misfolding

Since J. Cuillé and P. L. Chelle successfully transmitted scrapie between sheep by experi- mental inoculation in 1936 and D. C. Gajdusek kuru and Creutzfeldt-Jakob disease to chimpanzee in 1966 and 1968, respectively, the nature of the agents causing these " slow virus diseases " remains a mystery. In 1982, S. Prusiner called them " PRIONs " (for " PROteinaceous INfectious particles ") because they appeared lacking the nucleic acids that would classify them viruses. Although infectious or genetic mechanisms were seldom found, most of the rare human PRION diseases appeared " sporadic ". They shared many clinical and neuropathological properties with human neurodegenerative diseases (slow development, prominent nervous system involvement, amyloid deposits, paucity of immune response) the mechanism of which was not considered usually infectious. In 1991, H. Braak showed, in Alzheimer's disease brain, the low spreading of neuropathological tau associated lesions along anatomic pathways. They appear long before the clinical signs. The abnor- mally misfolded proteins characteristics of many neurodegenerative diseases are thought to aggregate after an initial seeding. This leads to their cell-cell transmission and dissemina- tion through neuronal and extra-neuronalpathways, which unexpected extent is under study. Whether the seeding is infectious or not remains debated. This new paradigm for unders- tanding their natural history and phenotypic diversity, which has already led to assess the diagnostic value of skin biopsy, should open the door to new therapeutic approach.