Prions are transmissible, self-replicating protein conformations that cause neurodegenerative diseases in mammals, but function as beneficial genetic elements in fungi.
The generation of synthetic prions provides definitive support for the prion hypothesis.
Beneficial fungal prions are regulated by protein-remodelling factors (such as Hsp104) and molecular chaperones (such as Hsp40).
The yeast prion [PSI+] confers evolvability and phenotypic plasticity, which impart selective advantages
Prions that mimic loss-of-function mutations might act as evolutionary capacitors.
Glutamine (Gln)/asparagine (Asn)-rich domains of yeast prions confer all aspects of prion behaviour, and are broadly distributed in many proteins of plants, fungi and metazoa, indicating that prions might be more common than previously thought.
CPEB prions might function in the formation of long-term memory.
Prions might also be involved in the construction of transcriptional memory and genome-wide expression patterns.
Changes in protein conformation drive most biological processes, but none have seized the imagination of scientists and the public alike as have the self-replicating conformations of prions. Prions transmit lethal neurodegenerative diseases by means of the food chain. However, self-replicating protein conformations can also constitute molecular memories that transmit genetic information. Here, we showcase definitive evidence for the prion hypothesis and discuss examples in which prion-encoded heritable information has been harnessed during evolution to confer selective advantages. We then describe situations in which prion-enciphered events might have essential roles in long-term memory formation, transcriptional memory and genome-wide expression patterns.
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James, L. C. & Tawfik, D. S. Conformational diversity and protein evolution — a 60-year-old hypothesis revisited. Trends Biochem. Sci. 28, 361–368 (2003).
Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).
Wickner, R. B. [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. Science 264, 566–569 (1994).
Si, K., Lindquist, S. & Kandel, E. R. A neuronal isoform of the Aplysia CPEB has prion-like properties. Cell 115, 879–891 (2003). This paper shows that ApCPEB can function as a prion in yeast, and that the prion conformation is the most active in stimulating translation of CPEB-regulated mRNA. Together with data from reference 99, the authors propose that the formation of ApCPEB prions in specifically stimulated synapses helps to maintain long-term synaptic changes that are associated with memory storage.
Prusiner, S. B. Prion Biology and Diseases (Cold Spring Harbor Laboratory Press, New York, 2004).
Uptain, S. M. & Lindquist, S. Prions as protein-based genetic elements. Annu. Rev. Microbiol. 56, 703–741 (2002).
Wickner, R. B., Liebman, S. W. & Saupe, S. J. in Prion Biology and Diseases (ed. Prusiner, S. B.) 305–372 (Cold Spring Harbor Laboratory Press New York, 2004).
Chien, P., Weissman, J. S. & DePace, A. H. Emerging principles of conformation-based prion inheritance. Annu. Rev. Biochem. 73, 617–656 (2004).
Alper, T., Cramp, W. A., Haig, D. A. & Clarke, M. C. Does the agent of scrapie replicate without nucleic acid? Nature 214, 764–766 (1967).
Griffith, J. S. Self-replication and scrapie. Nature 215, 1043–1044 (1967).
Prusiner, S. B. et al. Scrapie prions aggregate to form amyloid-like birefringent rods. Cell 35, 349–358 (1983).
Kong, Q. et al. in Prion Biology and Diseases (ed. Prusiner, S. B.) 673–775 (Cold Spring Laboratory Press New York, 2004).
Bueler, H. et al. Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347 (1993).
Brandner, S. et al. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379, 339–343 (1996).
Safar, J. et al. Eight prion strains have PrPSc molecules with different conformations. Nature Med. 4, 1157–1165 (1998).
Cox, B. S. [PSI], a cytoplasmic suppressor of super-suppression in yeast. Heredity 20, 505–521 (1965).
Lacroute, F. Non-Mendelian mutation allowing ureidosuccinic acid uptake in yeast. J. Bacteriol. 106, 519–522 (1971).
Sondheimer, N. & Lindquist, S. Rnq1: an epigenetic modifier of protein function in yeast. Mol. Cell 5, 163–172 (2000).
Santoso, A., Chien, P., Osherovich, L. Z. & Weissman, J. S. Molecular basis of a yeast prion species barrier. Cell 100, 277–288 (2000).
Osherovich, L. Z., Cox, B. S., Tuite, M. F. & Weissman, J. S. Dissection and design of yeast prions. PLoS Biol. 2, E86 (2004).
Coustou, V., Deleu, C., Saupe, S. & Begueret, J. The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. Proc. Natl Acad. Sci. USA 94, 9773–9778 (1997).
Baskakov, I. V., Legname, G., Baldwin, M. A., Prusiner, S. B. & Cohen, F. E. Pathway complexity of prion protein assembly into amyloid. J. Biol. Chem. 277, 21140–21148 (2002).
Glover, J. R. et al. Self-seeded fibres formed by Sup35, the protein determinant of [PSI+], a heritable prion-like factor of S. cerevisiae. Cell 89, 811–819 (1997).
Taylor, K. L., Cheng, N., Williams, R. W., Steven, A. C. & Wickner, R. B. Prion domain initiation of amyloid formation in vitro from native Ure2p. Science 283, 1339–1343 (1999).
Maddelein, M. L., Dos Reis, S., Duvezin-Caubet, S., Coulary-Salin, B. & Saupe, S. J. Amyloid aggregates of the HET-s prion protein are infectious. Proc. Natl Acad. Sci. USA 99, 7402–7407 (2002).
Patino, M. M., Liu, J. J., Glover, J. R. & Lindquist, S. Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 273, 622–626 (1996).
Paushkin, S. V., Kushnirov, V. V., Smirnov, V. N. & Ter-Avanesyan, M. D. Propagation of the yeast prion-like [PSI+] determinant is mediated by oligomerization of the SUP35-encoded polypeptide chain release factor. EMBO J. 15, 3127–3134 (1996).
Masison, D. C. & Wickner, R. B. Prion-inducing domain of yeast Ure2p and protease resistance of Ure2p in prion-containing cells. Science 270, 93–95 (1995).
Balguerie, A. et al. Domain organization and structure-function relationship of the HET-s prion protein of Podospora anserina. EMBO J. 22, 2071–2081 (2003).
Speransky, V. V., Taylor, K. L., Edskes, H. K., Wickner, R. B. & Steven, A. C. Prion filament networks in [URE3] cells of Saccharomyces cerevisiae. J. Cell Biol. 153, 1327–1336 (2001).
Kimura, Y., Koitabashi, S. & Fujita, T. Analysis of yeast prion aggregates with amyloid-staining compound in vivo. Cell Struct. Funct. 28, 187–193 (2003).
Kryndushkin, D. S., Alexandrov, I. M., Ter-Avanesyan, M. D. & Kushnirov, V. V. Yeast [PSI+] prion aggregates are formed by small Sup35 polymers fragmented by Hsp104. J. Biol. Chem. 278, 49636–49643 (2003).
King, C. Y. & Diaz-Avalos, R. Protein-only transmission of three yeast prion strains. Nature 428, 319–323 (2004).
Serio, T. R. et al. Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science 289, 1317–1321 (2000).
Dobson, C. M. Protein folding and misfolding. Nature 426, 884–890 (2003).
Tanaka, M., Chien, P., Naber, N., Cooke, R. & Weissman, J. S. Conformational variations in an infectious protein determine prion strain differences. Nature 428, 323–328 (2004). References 33 and 36 provide definitive evidence for the yeast prion hypothesis. They establish beyond doubt that [ PSI+] is caused by self-replicating conformers of Sup35, and that distinct, stably propagating Sup35 conformations underpin different [ PSI+] variants.
Legname, G. et al. Synthetic mammalian prions. Science 305, 673–676 (2004).
DePace, A. H. & Weissman, J. S. Origins and kinetic consequences of diversity in Sup35 yeast prion fibres. Nature Struct. Biol. 9, 389–396 (2002).
Baxa, U., Speransky, V., Steven, A. C. & Wickner, R. B. Mechanism of inactivation on prion conversion of the Saccharomyces cerevisiae Ure2 protein. Proc. Natl Acad. Sci. USA 99, 5253–5260 (2002).
Fink, G. R. A transforming principle. Cell 120, 153–154 (2005).
Kaneko, K. et al. A synthetic peptide initiates Gerstmann-Straussler-Scheinker (GSS) disease in transgenic mice. J. Mol. Biol. 295, 997–1007 (2000).
Legname, G. et al. Strain-specified characteristics of mouse synthetic prions. Proc. Natl Acad. Sci. USA 102, 2168–2173 (2005). References 37, 41 and 42 provide the initial foundations of definitive evidence for the mammalian prion hypothesis.
Edskes, H. K. & Wickner, R. B. Transmissible spongiform encephalopathies: prion proof in progress. Nature 430, 977–979 (2004).
Goudsmit, J. et al. Evidence for and against the transmissibility of Alzheimer disease. Neurology 30, 945–950 (1980).
West, M. W. et al. De novo amyloid proteins from designed combinatorial libraries. Proc. Natl Acad. Sci. USA 96, 11211–11216 (1999).
Medawar, P. B. An Unsolved Problem of Biology (H. K. Lewis, London, 1952).
Chernoff, Y. O. et al. Evolutionary conservation of prion-forming abilities of the yeast Sup35 protein. Mol. Microbiol. 35, 865–876 (2000).
Nakayashiki, T., Ebihara, K., Bannai, H. & Nakamura, Y. Yeast [PSI+] 'prions' that are crosstransmissible and susceptible beyond a species barrier through a quasi-prion state. Mol. Cell 7, 1121–1130 (2001).
Baudin-Baillieu, A., Fernandez-Bellot, E., Reine, F., Coissac, E. & Cullin, C. Conservation of the prion properties of Ure2p through evolution. Mol. Biol. Cell 14, 3449–3458 (2003).
Jensen, M. A., True, H. L., Chernoff, Y. O. & Lindquist, S. Molecular population genetics and evolution of a prion-like protein in Saccharomyces cerevisiae. Genetics 159, 527–535 (2001).
Lindquist, S. Mad cows meet psi-chotic yeast: the expansion of the prion hypothesis. Cell 89, 495–498 (1997).
Berson, J. F. et al. Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis. J. Cell Biol. 161, 521–533 (2003).
Mackay, J. P. et al. The hydrophobin EAS is largely unstructured in solution and functions by forming amyloid-like structures. Structure 9, 83–91 (2001).
Chapman, M. R. et al. Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295, 851–855 (2002).
Kranenburg, O. et al. Tissue-type plasminogen activator is a multiligand cross-β structure receptor. Curr. Biol. 12, 1833–1839 (2002). References 52–55 provide fascinating examples of beneficial amyloid conformers.
Gebbink, M. F., Voest, E. E. & Reijerkerk, A. Do antiangiogenic protein fragments have amyloid properties? Blood 104, 1601–1605 (2004).
Nucifora, F. C. Jr. et al. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291, 2423–2428 (2001).
Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003).
Chernoff, Y. O., Lindquist, S. L., Ono, B., Inge-Vechtomov, S. G. & Liebman, S. W. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [PSI+]. Science 268, 880–884 (1995).
Moriyama, H., Edskes, H. K. & Wickner, R. B. [URE3] prion propagation in Saccharomyces cerevisiae: requirement for chaperone Hsp104 and curing by overexpressed chaperone Ydj1p. Mol. Cell Biol. 20, 8916–8922 (2000).
Sondheimer, N., Lopez, N., Craig, E. A. & Lindquist, S. The role of Sis1 in the maintenance of the [RNQ+] prion. EMBO J. 20, 2435–2442 (2001).
Lopez, N., Aron, R. & Craig, E. A. Specificity of class II Hsp40 Sis1 in maintenance of yeast prion [RNQ+]. Mol. Biol. Cell. 14, 1172–1181 (2003).
Mallucci, G. et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302, 871–874 (2003). This remarkable paper shows that prion diseases might be treated post infection by downregulating endogenous PrP.
Dorn, G. et al. siRNA relieves chronic neuropathic pain. Nucleic Acids Res. 32, e49 (2004).
Xia, H. et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nature Med. 10, 816–820 (2004).
Komar, A. A. et al. Internal initiation drives the synthesis of Ure2 protein lacking the prion domain and affects [URE3] propagation in yeast cells. EMBO J. 22, 1199–1209 (2003).
True, H. L. & Lindquist, S. L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000).
Uptain, S. M., Sawicki, G. J., Caughey, B. & Lindquist, S. Strains of [PSI+] are distinguished by their efficiencies of prion-mediated conformational conversion. EMBO J. 20, 6236–6245 (2001).
Bidou, L. et al. Nonsense-mediated decay mutants do not affect programmed-1 frameshifting. RNA 6, 952–961 (2000).
Kellis, M., Patterson, N., Endrizzi, M., Birren, B. & Lander, E. S. Sequencing and comparison of yeast species to identify genes and regulatory elements. Nature 423, 241–254 (2003).
True, H. L., Berlin, I. & Lindquist, S. L. Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits. Nature 431, 184–187 (2004). Together with reference 67, this paper makes a compelling case for [ PSI+] as a beneficial prion.
Eaglestone, S. S., Cox, B. S. & Tuite, M. F. Translation termination efficiency can be regulated in Saccharomyces cerevisiae by environmental stress through a prion-mediated mechanism. EMBO J. 18, 1974–1981 (1999).
Orr, H. A. The population genetics of adaptation: the distribution of factors fixed during adaptive evolution. Evolution 52, 935–949 (1998).
Partridge, L. & Barton, N. H. Evolving evolvability. Nature 407, 457–458 (2000).
Brookfield, J. F. Evolution: the evolvability enigma. Curr. Biol. 11, R106–R108 (2001).
Kirschner, M. & Gerhart, J. Evolvability. Proc. Natl Acad. Sci. USA 95, 8420–8427 (1998).
Masel, J. & Bergman, A. The evolution of the evolvability properties of the yeast prion [PSI+]. Evolution Int. J. Org. Evolution 57, 1498–1512 (2003). A convincing modelling study suggesting that [ PSI+] has probably been maintained owing to the evolvability properties that it confers.
Earl, D. J. & Deem, M. W. Evolvability is a selectable trait. Proc. Natl Acad. Sci. USA 101, 11531–11536 (2004).
Resende, C. G., Outeiro, T. F., Sands, L., Lindquist, S. & Tuite, M. F. Prion protein gene polymorphisms in Saccharomyces cerevisiae. Mol. Microbiol. 49, 1005–1017 (2003).
Lindquist, S. But yeast prion offers clues about evolution. Nature 408, 17–18 (2000).
Harrison, P. et al. A small reservoir of disabled ORFs in the yeast genome and its implications for the dynamics of proteome evolution. J. Mol. Biol. 316, 409–419 (2002).
Namy, O., Duchateau-Nguyen, G. & Rousset, J. P. Translational readthrough of the PDE2 stop codon modulates cAMP levels in Saccharomyces cerevisiae. Mol. Microbiol. 43, 641–652 (2002).
Dalstra, H. J., Swart, K., Debets, A. J., Saupe, S. J. & Hoekstra, R. F. Sexual transmission of the [Het-s] prion leads to meiotic drive in Podospora anserina. Proc. Natl Acad. Sci. USA 100, 6616–6621 (2003).
Derkatch, I. L., Bradley, M. E., Zhou, P., Chernoff, Y. O. & Liebman, S. W. Genetic and environmental factors affecting the de novo appearance of the [PSI+] prion in Saccharomyces cerevisiae. Genetics 147, 507–519 (1997).
Derkatch, I. L., Bradley, M. E., Hong, J. Y. & Liebman, S. W. Prions affect the appearance of other prions: the story of [PIN+]. Cell 106, 171–182 (2001).
Bradley, M. E., Edskes, H. K., Hong, J. Y., Wickner, R. B. & Liebman, S. W. Interactions among prions and prion 'strains' in yeast. Proc. Natl Acad. Sci. USA 99 (Suppl. 4), 16392–16399 (2002).
Salmon, J. M. & Barre, P. Improvement of nitrogen assimilation and fermentation kinetics under enological conditions by derepression of alternative nitrogen-assimilatory pathways in an industrial Saccharomyces cerevisiae strain. Appl. Environ. Microbiol. 64, 3831–3837 (1998).
Crespo, J. L., Daicho, K., Ushimaru, T. & Hall, M. N. The GATA transcription factors GLN3 and GAT1 link TOR to salt stress in Saccharomyces cerevisiae. J. Biol. Chem. 276, 34441–34444 (2001).
Bergman, A. & Siegal, M. L. Evolutionary capacitance as a general feature of complex gene networks. Nature 424, 549–552 (2003). This remarkable study indicates that many, if not all, genes expose phenotypic variation when functionally compromised, and that the availability of loss-of-function mutations expedites adaptation to new phenotypic optima. Therefore, evolutionary capacitors might be more widespread than previously anticipated.
Hughes, T. R. et al. Functional discovery via a compendium of expression profiles. Cell 102, 109–126 (2000).
Sangster, T. A., Lindquist, S. & Queitsch, C. Under cover: causes, effects and implications of Hsp90-mediated genetic capacitance. Bioessays 26, 348–362 (2004).
Michelitsch, M. D. & Weissman, J. S. A census of glutamine/asparagine-rich regions: implications for their conserved function and the prediction of novel prions. Proc. Natl Acad. Sci. USA 97, 11910–11915 (2000).
Harrison, P. M. & Gerstein, M. A method to assess compositional bias in biological sequences and its application to prion-like glutamine/asparagine-rich domains in eukaryotic proteomes. Genome Biol. 4, R40 (2003).
Flechsig, E. et al. Prion protein devoid of the octapeptide repeat region restores susceptibility to scrapie in PrP knockout mice. Neuron 27, 399–408 (2000).
Liu, J. J. & Lindquist, S. Oligopeptide-repeat expansions modulate 'protein-only' inheritance in yeast. Nature 400, 573–576 (1999).
Krishnan, R. & Lindquist, S. L. New structural insights on a yeast prion illuminate nucleation and strain diversity. Nature (in the press). This paper defines which regions of the Sup35 prion domain make intermolecular contacts in assembled prion fibres. It also describes how variations in these intermolecular contacts facilitate the construction of different prion variants.
Ross, E. D., Baxa, U. & Wickner, R. B. Scrambled prion domains form prions and amyloid. Mol. Cell Biol. 24, 7206–7213 (2004).
Uversky, V. N. & Fink, A. L. Conformational constraints for amyloid fibrillation: the importance of being unfolded. Biochim. Biophys. Acta 1698, 131–153 (2004).
Si, K. et al. A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in Aplysia. Cell 115, 893–904 (2003). This paper establishes that neurotransmitter cues upregulate ApCPEB at specific synapses, and that consequent ApCPEB-stimulated translation has a crucial role in the maintenance of synaptic growth associated with long-term facilitation. Together with reference 4, this paper makes a compelling argument that ApCPEB prions function in long-term memory formation.
Bailey, C. H., Kandel, E. R. & Si, K. The persistence of long-term memory: a molecular approach to self-sustaining changes in learning-induced synaptic growth. Neuron 44, 49–57 (2004).
Lisman, J., Schulman, H. & Cline, H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nature Rev. Neurosci. 3, 175–190 (2002).
Bhalla, U. S. & Iyengar, R. Emergent properties of networks of biological signaling pathways. Science 283, 381–387 (1999).
Thayer, M. J. et al. Positive autoregulation of the myogenic determination gene MyoD1. Cell 58, 241–248 (1989).
Way, J. C. & Chalfie, M. The mec-3 gene of Caenorhabditis elegans requires its own product for maintained expression and is expressed in three neuronal cell types. Genes Dev. 3, 1823–1833 (1989).
Mendez, R. & Richter, J. D. Translational control by CPEB: a means to the end. Nature Rev. Mol. Cell Biol. 2, 521–529 (2001).
Uversky, V. N., Gillespie, J. R. & Fink, A. L. Why are 'natively unfolded' proteins unstructured under physiologic conditions? Proteins 41, 415–427 (2000).
Sajikumar, S. & Frey, J. U. Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD. Neurobiol. Learn. Mem. 82, 12–25 (2004).
Theis, M., Si, K. & Kandel, E. R. Two previously undescribed members of the mouse CPEB family of genes and their inducible expression in the principal cell layers of the hippocampus. Proc. Natl Acad. Sci. USA 100, 9602–9607 (2003).
Li, L. & Lindquist, S. Creating a protein-based element of inheritance. Science 287, 661–664 (2000).
Ter-Avanesyan, M. D. et al. Deletion analysis of the SUP35 gene of the yeast Saccharomyces cerevisiae reveals two non-overlapping functional regions in the encoded protein. Mol. Microbiol. 7, 683–692 (1993).
Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the polycomb and trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).
Kim, C. A., Gingery, M., Pilpa, R. M. & Bowie, J. U. The SAM domain of polyhomeotic forms a helical polymer. Nature Struct. Biol. 9, 453–457 (2002).
Qiao, F. et al. Derepression by depolymerization; structural insights into the regulation of Yan by Mae. Cell 118, 163–173 (2004).
Roberts, C. W. & Orkin, S. H. The SWI/SNF complex — chromatin and cancer. Nature Rev. Cancer 4, 133–142 (2004).
Sudarsanam, P., Iyer, V. R., Brown, P. O. & Winston, F. Whole-genome expression analysis of snf/swi mutants of Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 97, 3364–3369 (2000).
Gilks, N. et al. Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol. Biol. Cell 15, 5383–5398 (2004).
Roberts, B. T. & Wickner, R. B. Heritable activity: a prion that propagates by covalent autoactivation. Genes Dev. 17, 2083–2087 (2003).
Collin, P., Beauregard, P. B., Elagoz, A. & Rokeach, L. A. A non-chromosomal factor allows viability of Schizosaccharomyces pombe lacking the essential chaperone calnexin. J. Cell Sci. 117, 907–918 (2004).
Ball, A. J., Wong, D. K. & Elliott, J. J. Glucosamine resistance in yeast. I. A preliminary genetic analysis. Genetics 84, 311–317 (1976).
Silar, P., Haedens, V., Rossignol, M. & Lalucque, H. Propagation of a novel cytoplasmic, infectious and deleterious determinant is controlled by translational accuracy in Podospora anserina. Genetics 151, 87–95 (1999).
Talloczy, Z., Menon, S., Neigeborn, L. & Leibowitz, M. J. The [KIL-d] cytoplasmic genetic element of yeast results in epigenetic regulation of viral M double-stranded RNA gene expression. Genetics 150, 21–30 (1998).
Volkov, K. V. et al. Novel non-Mendelian determinant involved in the control of translation accuracy in Saccharomyces cerevisiae. Genetics 160, 25–36 (2002).
Derkatch, I. L., Chernoff, Y. O., Kushnirov, V. V., Inge-Vechtomov, S. G. & Liebman, S. W. Genesis and variability of [PSI] prion factors in Saccharomyces cerevisiae. Genetics 144, 1375–1386 (1996).
Ter-Avanesyan, M. D., Dagkesamanskaya, A. R., Kushnirov, V. V. & Smirnov, V. N. The SUP35 omnipotent suppressor gene is involved in the maintenance of the non-Mendelian determinant [PSI+] in the yeast Saccharomyces cerevisiae. Genetics 137, 671–676 (1994).
Liu, J. J., Sondheimer, N. & Lindquist, S. L. Changes in the middle region of Sup35 profoundly alter the nature of epigenetic inheritance for the yeast prion [PSI+]. Proc. Natl Acad. Sci. USA 99 (Suppl. 4), 16446–16453 (2002).
Bagriantsev, S. & Liebman, S. W. Specificity of prion assembly in vivo. [PSI+] and [PIN+] form separate structures in yeast. J. Biol. Chem. 279, 51042–51048 (2004).
Schlumpberger, M., Prusiner, S. B. & Herskowitz, I. Induction of distinct [URE3] yeast prion strains. Mol. Cell Biol. 21, 7035–7046 (2001).
Osherovich, L. Z. & Weissman, J. S. Multiple Gln/Asn-rich prion domains confer susceptibility to induction of the yeast [PSI+] prion. Cell 106, 183–194 (2001).
Derkatch, I. L. et al. Effects of Q/N-rich, polyQ, and non-polyQ amyloids on the de novo formation of the [PSI+]prion in yeast and aggregation of Sup35 in vitro. Proc. Natl Acad. Sci. USA 101, 12934–12939 (2004).
Derkatch, I. L. et al. Dependence and independence of [PSI+] and [PIN+]: a two-prion system in yeast? EMBO J. 19, 1942–1952 (2000).
Bradley, M. E. & Liebman, S. W. Destabilizing interactions among [PSI+] and [PIN+] yeast prion variants. Genetics 165, 1675–1685 (2003).
Baker, H. F., Ridley, R. M., Duchen, L. W., Crow, T. J. & Bruton, C. J. Induction of β(A4)-amyloid in primates by injection of Alzheimer's disease brain homogenate. Comparison with transmission of spongiform encephalopathy. Mol. Neurobiol. 8, 25–39 (1994).
Lundmark, K. et al. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc. Natl Acad. Sci. USA 99, 6979–6984 (2002).
Xing, Y. et al. Induction of protein conformational change in mouse senile amyloidosis. J. Biol. Chem. 277, 33164–33169 (2002).
Prinz, M. et al. Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425, 957–962 (2003).
Tanaka, M., Chien, P., Yonekura, K. & Weissman, J. S. Mechanism of cross-species prion transmission; an infectious conformation compatible with two highly divergent yeast prion proteins. Cell 121, 49–62 (2005).
Shorter, J. & Lindquist, S. Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science 304, 1793–1797 (2004). A delineation of how Hsp104 directly regulates Sup35 prion conformers.
Scheibel, T. et al. Conducting nanowires built by controlled self-assembly of amyloid fibres and selective metal deposition. Proc. Natl Acad. Sci. USA 100, 4527–4532 (2003).
Masel, J., Jansen, V. A. & Nowak, M. A. Quantifying the kinetic parameters of prion replication. Biophys. Chem. 77, 139–152 (1999).
Lee, D. H., Granja, J. R., Martinez, J. A., Severin, K. & Ghadiri, M. R. A self-replicating peptide. Nature 382, 525–528 (1996).
Lee, D. H., Severin, K., Yokobayashi, Y. & Ghadiri, M. R. Emergence of symbiosis in peptide self-replication through a hypercyclic network. Nature 390, 591–594 (1997).
Saghatelian, A., Yokobayashi, Y., Soltani, K. & Ghadiri, M. R. A chiroselective peptide replicator. Nature 409, 797–801 (2001). References 140–142 describe a remarkable set of short α -helical peptides that can undergo chemical and conformational replication, and which might even help to explain the origins of homochirality.
Pan, K. M. et al. Conversion of α-helices into β-sheets features in the formation of the scrapie prion proteins. Proc. Natl Acad. Sci. USA 90, 10962–10966 (1993).
Wille, H., Zhang, G. F., Baldwin, M. A., Cohen, F. E. & Prusiner, S. B. Separation of scrapie prion infectivity from PrP amyloid polymers. J. Mol. Biol. 259, 608–621 (1996).
Parsell, D. A., Kowal, A. S., Singer, M. A. & Lindquist, S. Protein disaggregation mediated by heat-shock protein Hsp104. Nature 372, 475–478 (1994).
Glover, J. R. & Lindquist, S. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94, 73–82 (1998).
Wegrzyn, R. D., Bapat, K., Newnam, G. P., Zink, A. D. & Chernoff, Y. O. Mechanism of prion loss after Hsp104 inactivation in yeast. Mol. Cell Biol. 21, 4656–4669 (2001).
Hattendorf, D. A. & Lindquist, S. L. Analysis of the AAA sensor-2 motif in the C-terminal ATPase domain of Hsp104 with a site-specific fluorescent probe of nucleotide binding. Proc. Natl Acad. Sci. USA 99, 2732–2737 (2002).
Hattendorf, D. A. & Lindquist, S. L. Cooperative kinetics of both Hsp104 ATPase domains and interdomain communication revealed by AAA sensor-1 mutants. EMBO J. 21, 12–21 (2002).
Grimminger, V., Richter, K., Imhof, A., Buchner, J. & Walter, S. The prion curing agent guanidinium chloride specifically inhibits ATP hydrolysis by Hsp104. J. Biol. Chem. 279, 7378–7383 (2004).
Ripaud, L., Maillet, L. & Cullin, C. The mechanisms of [URE3] prion elimination demonstrate that large aggregates of Ure2p are dead-end products. EMBO J. 22, 5251–5259 (2003).
Collins, S. R., Douglass, A., Vale, R. D. & Weissman, J. S. Mechanism of prion propagation: amyloid growth occurs by monomer addition. PLoS Biol. 2, e321 (2004).
Inoue, Y., Taguchi, H., Kishimoto, A. & Yoshida, M. Hsp104 binds to yeast Sup35 prion fibre but needs other factor(s) to sever it. J. Biol. Chem. 279, 52319–52323 (2004).
Ferreira, P. C., Ness, F., Edwards, S. R., Cox, B. S. & Tuite, M. F. The elimination of the yeast [PSI+] prion by guanidine hydrochloride is the result of Hsp104 inactivation. Mol. Microbiol. 40, 1357–1369 (2001).
Shorter, J. & Lindquist, S. Navigating the ClpB channel to solution. Nature Struct. Mol. Biol. 12, 4–6 (2005).
Serio T. R. & Lindquist S. L. Protein-only inheritance in yeast: something to get [PSI+]-ched about. Trends Cell Biol. 10, 98–105 (2000).
Leeds, P., Peltz, S. W., Jacobson, A. & Culbertson, M. R. The product of the yeast UPF1 gene is required for rapid turnover of mRNAs containing a premature translational termination codon. Genes Dev. 5, 2303–2314 (1991).
Frischmeyer, P. A. et al. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science 295, 2258–2261 (2002).
Bence, N. F., Sampat, R. M. & Kopito, R. R. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 1552–155 (2001).
Venkatraman, P., Wetzel, R., Tanaka, M., Nukina, N. & Goldberg, A. L. Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol. Cell 14, 95–104 (2004).
Castilla, J., Saa, P., Hetz, C. & Soto, C. In vitro generation of infectious scrapie prions. Cell 121, 195–206 (2005).
Zou, W. Q. & Gambetti, P. From microbes to prions the final proof of the prion hypothesis. Cell 121, 155–157 (2005).
We thank Kent Matlack, Jessica Brown, Todd Sangster, Jens Tyedmers, Walker Jackson, Martin Dünnwald, Sven Heinrich and Ram Krishnan for invaluable comments on the manuscript. J.S. was supported by a Charles A. King Trust post-doctoral fellowship. S.L. was supported by a National Institutes of Health grant.
The authors declare no competing financial interests.
Saccharomyces genome database
Chronic Wasting Disease Alliance
UK Department for Environment Food and Rural Affairs Bovine Spongiform Encephalopathy website
- PHENOTYPIC SPACE
A multi-dimensional continuum of all possible phenotypes.
- ADAPTIVE LANDSCAPE
A graph of the average fitness of a population in relation to the frequencies of genotypes in the population.
Any of two or more isomers that differ only in their three dimensional conformation.
- CODICAL DOMAIN
The domain of natural selection dealing solely with self-replicating information as opposed to material entities.
Any cell with more than one nucleus and where the nuclei are not all of the same genetic constitution, or a tissue composed of such cells.
A general term for protein aggregates that accumulate as fibres of 7–10nm in diameter with common structural features including: β-pleated sheet conformation, resistance to detergents and proteases, and the ability to bind such dyes as Congo red and Thioflavin T and S.
Any substance (usually ions) that increases the transfer of apolar groups to water by decreasing the 'ordered' structure of water. Chaotropes alter secondary, tertiary and quaternary protein structure.
A proliferation on an inert surface of aggregated microbial colonies that have increased resistance to antimicrobial therapies. Biofilms contribute to many human infections.
A form of neurodegeneration involving the formation of large fluid-filled spaces (vacuoles) in the brain, which if widespread, induces a sponge-like appearance of the brain. This spongiform change is a general (but not universal) pathological hallmark of prion diseases.
- PURIFYING SELECTION
A mode of natural selection that preserves the adapted condition, and is observed as a large excess of synonymous substitutions over non-synonymous substitutions in functionally important genes.
- CRYPTIC GENETIC VARIATION
Existing genetic variation that makes no contribution to the normal range of phenotypes, but which can modify phenotypes in response to environmental change or the introduction of novel genetic elements.
Describing two or more individuals that possess exactly the same genotype.
- VALLEY CROSSING
The process of moving from one adaptive peak to another on an adaptive landscape by crossing a valley. Valleys correspond to genotypic frequencies at which average fitness is low.
- ADAPTIVE PEAK
A region in an adaptive landscape corresponding to genotypic frequencies at which the average fitness is high.
- MEIOTIC DRIVE
Any process that causes some alleles to be over-represented in gametes formed during meiosis.
- EVOLUTIONARY CAPACITOR
An entity (for example, Hsp90) that buffers genotypic variation under neutral conditions, thereby allowing the accumulation of hidden polymorphisms.
- LONG-TERM FACILITATION
The long-lasting increase in synaptic activity that contributes to long-term memory and results from prolonged or iterated exposure of synapses to neurotransmitters, which induce the synthesis of new proteins leading to the stabilization of new synaptic connections.
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Shorter, J., Lindquist, S. Prions as adaptive conduits of memory and inheritance. Nat Rev Genet 6, 435–450 (2005). https://doi.org/10.1038/nrg1616
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