Much evidence supports the hypothesis that the infectious agents of prion diseases are devoid of nucleic acid, and instead are composed of a specific infectious protein1. This protein, PrPSc, seems to be generated by template-induced conformational change of a normally expressed glycoprotein, PrPC (ref. 2). Although numerous studies have established the conversion of PrPC to PrPSc as the central pathogenic event of prion disease, it is unknown whether cellular factors other than PrPC might be required to stimulate efficient PrPSc production. We investigated the biochemical amplification of protease-resistant PrPSc-like protein (PrPres) using a modified version3 of the protein-misfolding cyclic amplification method4. Here we report that stoichiometric transformation of PrPC to PrPres in vitro requires specific RNA molecules. Notably, whereas mammalian RNA preparations stimulate in vitro amplification of PrPres, RNA preparations from invertebrate species do not. Our findings suggest that host-encoded stimulatory RNA molecules may have a role in the pathogenesis of prion disease. They also provide a practical approach to improve the sensitivity of diagnostic techniques based on PrPres amplification.
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The authors thank G. Saborio, C. Soto, V. Ambros, C. Cole and W. Wickner for helpful advice. This work was supported by the Burroughs Wellcome Fund Career Development Award, the Hitchcock Foundation, and an NIH Clinical Investigator Development Award.
The authors declare that they have no competing financial interests.
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Deleault, N., Lucassen, R. & Supattapone, S. RNA molecules stimulate prion protein conversion. Nature 425, 717–720 (2003). https://doi.org/10.1038/nature01979
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