RNA molecules stimulate prion protein conversion (original) (raw)

Nature volume 425, pages 717–720 (2003)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982)
    CAS PubMed Google Scholar
  2. Prusiner, S. B. (ed.) Prion Biology and Diseases (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1999)
  3. Lucassen, R., Nishina, K. & Supattapone, S. In vitro amplification of protease-resistant prion protein requires free sulfhydryl groups. Biochemistry 42, 4127–4135 (2003)
    Article CAS PubMed Google Scholar
  4. Saborio, G. P., Permanne, B. & Soto, C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411, 810–813 (2001)
    Article CAS PubMed Google Scholar
  5. Lockard, R. E. & Kumar, A. Mapping tRNA structure in solution using double-strand-specific ribonuclease V1 from cobra venom. Nucleic Acids Res. 9, 5125–5140 (1981)
    Article CAS PubMed PubMed Central Google Scholar
  6. Banks, G. R. A ribonuclease H from Ustilago maydis. Properties, mode of action and substrate specificity of the enzyme. Eur. J. Biochem. 47, 499–507 (1974)
    Article CAS PubMed Google Scholar
  7. Kocisko, D. A. et al. Cell-free formation of protease-resistant prion protein. Nature 370, 471–474 (1994)
    Article CAS PubMed Google Scholar
  8. Caughey, B., Horiuchi, M., Demaimay, R. & Raymond, G. J. Assays of protease-resistant prion protein and its formation. Methods Enzymol. 309, 122–133 (1999)
    Article CAS PubMed Google Scholar
  9. Derrington, E. et al. PrPC has nucleic acid chaperoning properties similar to the nucleocapsid protein of HIV-1. C. R. Acad. Sci. III 325, 17–23 (2002)
    CAS Google Scholar
  10. Moscardini, M. et al. Functional interactions of nucleocapsid protein of feline immunodeficiency virus and cellular prion protein with the viral RNA. J. Mol. Biol. 318, 149–159 (2002)
    Article CAS PubMed Google Scholar
  11. Gabus, C. et al. The prion protein has RNA binding and chaperoning properties characteristic of nucleocapsid protein NCP7 of HIV-1. J. Biol. Chem. 276, 19301–19309 (2001)
    Article CAS PubMed Google Scholar
  12. Gabus, C. et al. The prion protein has DNA strand transfer properties similar to retroviral nucleocapsid protein. J. Mol. Biol. 307, 1011–1021 (2001)
    Article CAS PubMed Google Scholar
  13. Nandi, P. K., Leclerc, E., Nicole, J. C. & Takahashi, M. DNA-induced partial unfolding of prion protein leads to its polymerisation to amyloid. J. Mol. Biol. 322, 153–161 (2002)
    Article CAS PubMed Google Scholar
  14. Cordeiro, Y. et al. DNA converts cellular prion protein into the β-sheet conformation and inhibits prion peptide aggregation. J. Biol. Chem. 276, 49400–49409 (2001)
    Article CAS PubMed Google Scholar
  15. Weissmann, C. A ‘unified theory’ of prion propagation. Nature 352, 679–683 (1991)
    Article CAS PubMed Google Scholar
  16. Chapon, C., Cech, T. R. & Zaug, A. J. Polyadenylation of telomerase RNA in budding yeast. RNA 3, 1337–1351 (1997)
    CAS PubMed PubMed Central Google Scholar

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Dartmouth Medical School, 7200 Vail Building, Hanover, New Hampshire, 03755, USA
    Nathan R. Deleault, Ralf W. Lucassen & Surachai Supattapone

Authors

  1. Nathan R. Deleault
    You can also search for this author inPubMed Google Scholar
  2. Ralf W. Lucassen
    You can also search for this author inPubMed Google Scholar
  3. Surachai Supattapone
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toSurachai Supattapone.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Deleault, N., Lucassen, R. & Supattapone, S. RNA molecules stimulate prion protein conversion.Nature 425, 717–720 (2003). https://doi.org/10.1038/nature01979

Download citation

This article is cited by