Abstract
The molecular mechanism that determines under physiological conditions transmissibility of the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD) is unknown. We report the synthesis of new human prion from the recombinant human prion protein expressed in bacteria in reaction seeded with sCJD MM1 prions and cofactor, ganglioside GM1. These synthetic human prions were infectious to transgenic mice expressing non-glycosylated human prion protein, causing neurologic dysfunction after 459 and 224 days in the first and second passage, respectively. The neuropathology, replication potency, and biophysical profiling suggest that a novel, particularly neurotoxic human prion strain was created. Distinct biological and structural characteristics of our synthetic human prions suggest that subtle changes in the structural organization of critical domains, some linked to posttranslational modifications of the pathogenic prion protein (PrPSc), play a crucial role as a determinant of human prion infectivity, host range, and targetting of specific brain structures in mice models.
Highlights
The molecular mechanism that determines under physiological conditions transmissibility of the most common human prion disease, sporadic Creutzfeldt-Jakob disease is unknown
Despite relatively low frequency of transmitted human prion diseases, they have gained considerable importance due to their long incubation time and high resistance of human prions to inactivation, posing unprecedented and challenging problems to disease control and public health[3]. These invariably fatal neurodegenerations are caused by a pathogenic protein, PrPSc4, which is a misfolded isoform of the normal cellular prion protein[5,6,7,8,9,10,11], PrPC
Our recent experiments indicate that replication of sporadic Creutzfeldt-Jakob disease (sCJD) prions is principally determined by growth rate of prion aggregates that is in turn controled by their specific structural features, and not by their confromational stability, as it is in yeast and some murine prions[16]
Summary
The molecular mechanism that determines under physiological conditions transmissibility of the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD) is unknown. A number of recent studies have demonstrated that infectious rodent prions can be generated in vitro from bacterially expressed recombinant mouse or Syrian hamster PrP19–23, and the infectivity titer of some of these preparations was very high[19,21] These studies played a fundamentally important role in providing the ultimate proof for the protein-only hypothesis of prion diseases[21,22,24,25,26,27]. Attempts to generate infectious synthetic human prions have not yet been successful, hindering efforts to comprehensive understanding of human prion diseases such as sCJD We bridge this gap, showing that human prions can be synthesized in vitro from bacterially expressed recombinant human PrP in a reaction seeded with sCJD MM1 prions in the presence of a novel cofactor, ganglioside GM1. These structural and functional insights provide a foundation for more complete understanding of the molecular basis of human prion formation and propagation
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