Yeast prions as a model of neurodegenerative infectious amyloidoses in humans



Several neurodegenerative diseases (so-called age-related diseases) in humans are associated with development of protein aggregates—amyloids. Prion diseases—kuru, Kreutzfeldt—Jakob and Gerstmann—Straussler—Sheinker diseases, fatal familial insomnia, etc.—are examples of infectious amyloidoses. A model system for investigation of mechanisms of amyloidogenesis and of its infectious nature had been developed as a result of yeast prion discovery. The existence of a prion network as an interaction of different prions identified in yeast is being confirmed recently as an interaction of different anyloids in humans. The potential danger of amyloidoses is conditioned by the very structure of almost all proteins containing fragments capable to be organized as β-sheets, which lead to their aggregation being exposed. Meanwhile, there are several well-defined examples of the adaptive value of amyloid aggregates: cytoplasmic incompatibility factor in Podosporaanserina, spider silk, cytoplasmic stress granules in mammals, prion form of CPEB protein responsible for the neuron activity in Aplisia, etc. These facts should be taken into consideration when seeking antiamyloid drugs. Discovery of protein inheritance in lower eukaryotes modifies our knowledge of the template principle significance in biology and adds a concept of conformational templates (II order templates) involved in reproduction of the three-dimensional structure of the supramolecular complexes in the cell.


amyloids prions neurodegenerative diseases yeast protein inheritance 


  1. Alberti, S., Halfman, R., King, O., Kapila, A., and Lindquist, S., A Systematic Survey Identifies Prions and Illuminates Sequence Features of Prionogenic Proteins, Cell, 2009, vol. 137, pp. 146–158.PubMedCrossRefGoogle Scholar
  2. Anderson, P. and Kedersha, N., Stressful Initiations, J. Cell Sci., 2002, vol. 115, pp. 3227–3234.PubMedGoogle Scholar
  3. Bremer, J., Baumann, F., Tiberi, C., Wessig, C., Fischer, H., Schwarz, P., Steele, A.D., Toyka, K.V., Nave, K.-A., Weis, J., and Aguzzi, A., Axonal Prion Protein Is Required for Peripheral Myelin Maintenance, Nature Neurosci., 2010, vol. 13, pp. 310–318.PubMedCrossRefGoogle Scholar
  4. Brown, J.C.S. and Lindquist, S., A Heritable Switch in Car- bon Source Utilization Driven by an Unusual Yeast Prion, Genes Dev., 2009, vol. 23, pp. 2320–2332.PubMedCrossRefGoogle Scholar
  5. Brundin, P., Melki, R., and Kopito, R., Prion-Like Trans-mission of Protein Aggregates in Neurodegenerative Diseases, Nature Revs., 2010, vol. 11, pp. 301–307.CrossRefGoogle Scholar
  6. Chernoff, Yu.O., Derkach, I.L., and Inge-Vechtomov, S.G., Multicopy SUP35 Gene Induces de-novo Appearance of psi-Like Factors in the Yeast Saccharomyces cerevisiae, Curr. Genet., 1993, vol. 24, pp. 268–270.PubMedCrossRefGoogle Scholar
  7. Chernov, Yu.O., Derkach, I.L., Dagkesamanskaya, A.R., Tikhomirova, V.L., Ter-Avanesyan, M.D., and Inge-Vechtomov, S.G., Nonsense-Suppression during Amplification of the Gene Coding for Protein Translation Factor, Dokl. Akad. Nauk SSSR, 1988, vol. 301, pp. 1227–1229.PubMedGoogle Scholar
  8. Coustou, V., Deleu, C., Saupe, S., and Begueret, J., The Protein Product of the Het-S Heterokaryon Incompatibility Gene of the Fungus Podospora anserine Behaves as a Prion Analog, Proc. Natl. Acad. Sci. USA, 1997, vol. 94, pp. 9773–9778.PubMedCrossRefGoogle Scholar
  9. Cox, B.S., Ψ, a Cytoplasmic Suppressor of Super-Suppression in Yeast, Heredity, 1965, vol. 20, pp. 505–521.CrossRefGoogle Scholar
  10. Crick, F., Central Dogma of Molecular Biology, Nature, 1970, vol. 227, pp. 561–563.PubMedCrossRefGoogle Scholar
  11. Crick, F.H.C., On Protein Synthesis, Symp. Soc. Exp. Biol., 1958, vol. 12, pp. 138–163.PubMedGoogle Scholar
  12. Derkatch, I.L., Bradeley, M.E., Hong, J.Y., and Liebman, S.W., Prions Affect the Appearance of Other Prions: The Story of [PIN +], Cell, 2001, vol. 106, pp. 171–182.PubMedCrossRefGoogle Scholar
  13. Du, Z., Park, K.W., Yu, H., Fan, Q., and Li, L., Newly Identified Prion Linked to the Chromatin Remodeling Factor Swi1 in Saccharomyces cerevisiae, Nat. Genet., 2008, vol. 40, pp. 460–465.PubMedCrossRefGoogle Scholar
  14. Fink, G.R., A Transforming Principle, Cell, 2005, vol. 120, pp. 153–154.PubMedCrossRefGoogle Scholar
  15. Galkin, A.P., Mironova, L.N., Zhuravleva, G.A., and Inge-Vechtomov, S.G., Yeast Prions, Mammalian Amyloidoses, and the Problem of Proteomic Networks, Genetika, 2006, vol. 42, pp. 1558–1570.PubMedGoogle Scholar
  16. Gilks, N., Kedersha, N., Ayodele, M., et al., Stress Granule Assembly Is Mediated by Prion-Like Aggregation of TIA-1, Mol. Biol. Cell, 2004, vol. 15, pp. 5383–5398.PubMedCrossRefGoogle Scholar
  17. Glover, J.R., Kowal, A.S., Schirmer, E.C., Patino, M.M., Liu, J.J., and Lindquist, S., Self-Seeded Fibers Formed by Sup35, the Protein Determinant of [PSI +], a Heritable Prion-Like Factor of S. cerevisiae, Cell, 1997, vol. 89, pp. 811–819.PubMedCrossRefGoogle Scholar
  18. Hagn, F., Eisolt, L., Hardy, J.G., Vendrely, C., Coles, M., Scheibel, T., and Kessler, H., A Conserved Spider Silk Domain Acts as a Molecular Switch that Controls Fiber Assembly, Nature, 2010, vol. 465, pp. 239–242.PubMedCrossRefGoogle Scholar
  19. Inge-Vechtomov, S.G. and Andrianova, V.M., Recessive Supersuppressors in Yeast, Genetika, 1970, vol. 6, pp. 103–116.Google Scholar
  20. Inge-Vechtomov, S.G., Borkhsenius, A.S., and Zadorskii, S.P., Protein Inheritance: the Conformational Templates and Epigenetics, Inform. Vestn. VOGiS, 2004, vol. 8, no. 2, pp. 60–66.Google Scholar
  21. Inge-Vechtomov, S.G., Prions of Yeast and the Central Dogma of Molecular Biology, Vestn. Ross. Akad. Nauk, 2000, vol. 70, pp. 195–202.Google Scholar
  22. Inge-Vechtomov, S.G., Reversions to the Prototrophicity in Yeasts that Require Adenine, Vestn. Len. Univ., Ser. 3: Biol., 1964, no. 2, pp. 112–116.Google Scholar
  23. Kajava, A.V., Baxa, L.D., Wickner, R.B., and Steven, A.C., AModel for Ure2p Prion Filaments and Other Amyloids: The Parallel Superpleated beta-Structure, Proc. Natl. Acad. Sci. USA, 2004, vol. 101, pp. 7885–7890.PubMedCrossRefGoogle Scholar
  24. King, C.-Y., Tittman, P., Gross, H., Geber, R., Aebi, M., and Wuthrich, K., Prion-Inducing Domain 2–114 of Yeast Sup35 Protein Transforms in vitro into Amyloid-Like Filaments, Proc. Natl. Acad. Sci. USA, 1997, vol. 94, pp. 6618–6622.PubMedCrossRefGoogle Scholar
  25. Kol’tsov, N.K., Nasledstvennye molekuly. 1928 (Hereditary Molecules. 1928), cited according to Organizatsiya kletki (Cell Organization), Gos. Izd. Biol. Med. Lit., Moscow, 1936, pp. 585–622.Google Scholar
  26. Luzatto, L. and Notaro, R., Haemoglobin’s Chaperone, Nature, 2002, vol. 417, pp. 704–705.CrossRefGoogle Scholar
  27. Maji, S.K., Perrin, M.H., Sawaya, M.R., Jessberger, S., Vadodaria, K., Rissman, R.A., Singru, P.S., Nilsson, K.P.R., Simon, R., Schubert, D., Eisenberg, D., Rivier, J., Sawchenko, P., Vale, W., and Riek, R., Functional Amyloids as Natural Storage of Peptide Hormones in Pituitary Secretory Granules, Science, 2009, vol. 325, pp. 328–332.PubMedCrossRefGoogle Scholar
  28. Michelitsch, M.D. and Weissman, J.S., A Census of Glutamine/Asparagines-Rich Regions: Implications for Their Conserved Function and the Prediction of Novel Prions, Proc. Natl. Acad. Sci. USA, 2000, vol. 97, pp. 11910–11915.PubMedCrossRefGoogle Scholar
  29. Morales, R., Estrada, L.D., Diaz-Espinoza, R., Morales-Scheihing, D., Jara, M.C., Castilla, J., and Soto, C., Molecular Cross-Talk between Misfolded Proteins in Animal Models of Alzheimer’s and Prion Diseases, J. Neurosci., 2010, vol. 30, pp. 4528–4535.PubMedCrossRefGoogle Scholar
  30. Nemecek, J., Nakayashiki, T., and Wickner, R.B., A Prion of Yeast Metacaspase Homolog (Mca1p) Detected by a Genetic Screen, Proc. Natl. Acad. Sci. USA, 2009, vol. 106, pp. 1892–1896.PubMedCrossRefGoogle Scholar
  31. Osherovich, L.Z. and Weissman, J.S., Multiple Gln/Asn-Rich Prion Domains Confer Susceptibility to Induction of the Yeast [PSI +] Prion, Cell, 2001, vol. 106, pp. 183–194.PubMedCrossRefGoogle Scholar
  32. Parry, H.B., Scrapie: A Transmissible and Hereditary Disease of Sheep, Heredity, 1962, vol. 17, pp. 75–105.PubMedCrossRefGoogle Scholar
  33. Patel, B.K., Gavin-Smyth, J., and Liebman, S.W., The Yeast Global Transcriptional Co-Repressor Protein Cyc8 Can Propagate as Prion, Nature Cell Biol., 2009, vol. 11, pp. 344–349.PubMedCrossRefGoogle Scholar
  34. Paushkin, S.V., Kushnirov, V.V., Smirnov, V.N., and Ter-Avanesyan, M.D., In vitro Propagation of the Prion-Like State of Yeast Sup35 Protein, Science, 1997, vol. 277, pp. 381–383.PubMedCrossRefGoogle Scholar
  35. Perutz, M.F., Finch, J.T., Berriman, J., and Lesk, A., Amyloid Fibers Are Water-Filled Nanotubes, Proc. Natl. Acad. Sci. USA, 2002, vol. 99, pp. 5591–5595.PubMedCrossRefGoogle Scholar
  36. Prusiner, S.B., Prions, Proc. Natl. Acad. Sci. USA, 1998, vol. 95, pp. 13363–13383.PubMedCrossRefGoogle Scholar
  37. Prusiner, S.B., Shattuck Lecture-Neurodegenerative Diseases and Prions, N. Engl. J. Med., 2001, vol. 344, pp. 1516–1526.PubMedCrossRefGoogle Scholar
  38. Riek, R., Infectious Alzheimer’s Disease?, Nature, 2006, vol. 444, pp. 429–431.PubMedCrossRefGoogle Scholar
  39. Rogoza, T., Goginashwili, A., Rodionova, S., Ivanov, M., Viktorovskaya, O., Rubel, A., Volkov, K., and Mironova, L., Non-Mendelian Determinant [ISP +] in Yeast Is a Nuclear-Residing Prion Form of the Global Transcriptional Regulator Sfp1, Proc. Natl. Acad. Sci. USA, 2010, vol. 107, pp. 10573–10577.PubMedCrossRefGoogle Scholar
  40. Schnabel, J., The Dark Side of Proteins, Nature, 2010, vol. 464, pp. 828–829.PubMedCrossRefGoogle Scholar
  41. Si, K., Choi, Y-B., White-Grindley, E., Majumdar, A., and Kandel, E.R., Aplisia CPEB Can Form Prion-Like Multimers in Sensory Neurons that Contribute to Long-Term Facilitation, Cell, 2010, vol. 140, pp. 421–435.PubMedCrossRefGoogle Scholar
  42. Si. K., Lindquist, S., and Kandel, E.R., A Neuronal Isoform of the Aplisia CPEB Has Prion-Like Properties, Cell, 2003, vol. 115, pp. 879–891.PubMedCrossRefGoogle Scholar
  43. Ter-Avanesyan, M.D., Kushnirov, V.V., Dagkesamanskaya, A.R., Didichenko, S.A., Chernoff, Yu.O., Inge-Vechtomov, S.G., and Smirnov, V.N., Deletion Analysis of the SUP35 Gene of the Yeast Saccharomyces Cerevisiae Reveals Two Nonoverlapping Functional Regions in the Encoded Protein, Mol. Microbiol., 1993, vol. 7, pp. 683–692.PubMedCrossRefGoogle Scholar
  44. Tuite, M.F., Mundy, C.R., and Cox, B.S., Agents that Cause a High Frequency of Genetic Change from [PSI +] to [PSI-] in Saccharomyces cerevisiae, Genetics, 1981, vol. 98, pp. 691–711.PubMedGoogle Scholar
  45. Vendruscolo, M. and Dobson, C., More Charges Against Aggregation, Nature, 2007, vol. 449, p. 555.PubMedCrossRefGoogle Scholar
  46. Volkov, K., Osipov, K., Valouev, I., Inge-Vechtomov, S., and Mironova, L., N-Terminal Extension of Saccharomyces cerevisiae Translation Termination Factor ERF3 Influences the Suppression Efficiency of Sup35 Mutations, FEMS Yeast Res., 2007, vol. 7, pp. 357–365.PubMedCrossRefGoogle Scholar
  47. Wickner, R.B., [URE3] as an Altered URE2 Protein: Evidence for a Prion Analog in Saccharomyces cerevisiae, Science, 1994, vol. 264, pp. 566–569.PubMedCrossRefGoogle Scholar
  48. Zhouravleva, G., Frolova, L., Le Goff, X., Le Guillec, R., Inge-Vechtomov, S.G., Kisselev, L., and Philippe, M., Termination of Translation in Eukaryotes Is Governed by Two Interacting Polypeptide Chain Release Factors eRF1 and eRF3, The EMBO J., 1995, vol. 14, pp. 4065–4072.Google Scholar

Copyright information

© Pleiades Publishing, Ltd. 2011

Authors and Affiliations

  1. 1.Vavilov Institute of General Genetics, St. Petersburg BranchSt. Petersburg State UniversitySt. PetersburgRussia

Personalised recommendations