BIOLOGY OF THE TRANSMISSIBLE SPONGIFORM E NCEPHALOPATHY AGENTS (PRIONS)

Transmissible subacute spongiform encephalopathies (TSE) are a group o f human and animal diseases which includes Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome (GSS), Kuru, fatal familial in somnia (FFI), scrapie in sheep and goat, mink and feline transmissible encephalopathy, chronic wasting disease, and bovine spongiforme encep halopathy (BSE). TSE are transmissible among individuals of the same s pecies and some of different species. These diseases stem from a speci fic category of agents that have biological and physicochemical charac teristics unlike other micro-organisms: they are known as transmissibl e spongiform encephalopathy agent (TSA), prions, or virinos. So far, d espite considerable progress made in the molecular biology toward the understanding of neurological injury, the nature of the TSA/prions rem ains unknown. TSE are characterised by the pathognomic accumulation, w ithin the central nervous system of the infected individual, of a norm al protein from the host organism, the PIP (prion protein). Difference s between the PrP isolated from normal individuals (PrP-c) and PrP iso lated from infected individuals (PrP-res) have been investigated. Ther e are no differences in the sequence in amino acids, and the secondary structure seems identical, but since normal PrP is totally degraded b y proteinase K pathological PrP resists to enzymatic digestion. One ca n therefore describe two PrP isoforms: a normal isoform, the PrP-c (c for cellular), sensitive to proteinase K and present in the normal ind ividual and in the infected patients or animals; and a pathological is oform, the PrP-res, resistant to proteinase K and present in amount pr oportional to the infectivity in the brains of infected individuals. T he presence of TSA/prions is detectable in the spleens of infected ani mals early after inoculation; it is then present in the CNS following a period not exceeding a half of the total length of the experimental disease. In the CNS, PrP-res is the origin of spongiosis and gliosis t hat are observed in infected individuals. A double causality ''infecti ous'' and genetic, of these diseases can be derived from the various i deas currently accepted Indeed the genetic basis of some familial form s has now been confirmed and transmissibility has been proven in natur al situations such as the outbreak of CJD among children treated with extractive growth hormone and the recent surge of a new disease decima ting British cattle, the bovine spongiform subacute encephalopathy, or mad cow disease. In TSE affected individuals, PrP has a key role in t he incubation time and in the species barrier.