The key molecular event in human cerebral
proteinopathies, which include Alzheimer's, Parkinson's and Huntington's diseases, is the structural conversion of a specific host
protein into a β-sheet-rich conformer. With regards to this common mechanism, it appears difficult to explain the outstanding infectious properties attributed to PrP(Sc), the hallmark of another intriguing family of cerebral
proteinopathies known as
transmissible spongiform encephalopathies (TSE) or
prion diseases. The infectious PrP(Sc) or "
prion" is thought to be composed solely of a misfolded form of the otherwise harmless cellular
prion protein (PrP(c)). To gain insight into this unique situation, we used the 263K
scrapie hamster model to search for a putative PrP(Sc)-associated factor that contributes to the infectivity of PrP(Sc)
amyloid. In a rigorously controlled set of experiments that included several bioassays, we showed that originally innocuous recombinant
prion protein (recPrP) equivalent to PrP(c) is capable of initiating
prion disease in hamsters when it is converted to a
prion-like conformation (β-sheet-rich) in the presence of
RNA purified from
scrapie-associated fibril (
SAF) preparations. Analysis of the recPrP-
RNA infectious mixture reveals the presence of 2 populations of small RNAs of approximately 27 and 55
nucleotides. These unprecedented findings are discussed in light of the distinct relationship that may exist between this
RNA material and the 2
biological properties, infectivity and strain features, attributed to
prion amyloid.