The Role of Functional Prions in the Persistence of Memory Storage

  • Eric R. KandelEmail author
  • Irina Derkatch
  • Elias Pavlopoulos
Part of the Research and Perspectives in Alzheimer's Disease book series (ALZHEIMER)


Cellular and molecular studies of both implicit and explicit memory suggest that experience-dependent modulation of synaptic strength and structure is a fundamental mechanism by which these memories are encoded and stored within the brain. Implicit and explicit memory share in common several molecular steps and an overall molecular logic. Both have two general stages are created in at least two stages: a short-term phase that does not require the synthesis of new protein and a long-term phase that does. Short-term memory involves covalent modification of preexisting proteins and changes in the strength of preexisting synaptic connections, while long-term memory requires transcriptional activation mediated by CREB and the growth of new connections. The distinction between short- and long-term memory and the recruitment of a CREB-mediated activation of gene expression leading to the growth of new synaptic connections have turned out to be almost universal. Maintenance of long-term memory involves, in addition, the functional prion CPEB that regulates local protein synthesis. The self-sustaining, prion-like, activation of CPEB3 appears to be a quite general mechanism for the perpetuation of memory.


Yeast Prion Local Protein Synthesis Synaptic Growth Cytoplasmic Polyadenylation Element Binding Protein Prion Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Eric R. Kandel and Elias Pavlopoulos are supported by the Howard Hughes Medical Institute. Irina Derkatch is supported by National Institutes of Health grant 7 R01 GM070934.


  1. Alberti S, Halfmann R, King O, Kapila A, Lindquist S (2009) A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137:146–158PubMedCrossRefGoogle Scholar
  2. Bally-Cuif L, Schatz WJ, Ho RK (1998) Characterization of the zebrafish Orb/CPEB-related RNA binding protein and localization of maternal components in the zebrafish oocyte. Mech Dev 77:31–47PubMedCrossRefGoogle Scholar
  3. Barco A, Alarcon JM, Kandel ER (2002) Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 108:689–703PubMedCrossRefGoogle Scholar
  4. Casadio A, Martin KC, Giustetto M, Zhu H, Chen M, Bartsch D, Bailey CH, Kandel ER (1999) A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99:221–237PubMedCrossRefGoogle Scholar
  5. Chang JS, Tan L, Wolf MR, Schedl P (2001) Functioning of the Drosophila orb gene in gurken mRNA localization and translation. Development 128:3169–3177PubMedGoogle Scholar
  6. Coustou V, Deleu C, Saupe S, Begueret J (1997) 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 94:9773–9778PubMedCrossRefGoogle Scholar
  7. Cox BS (1965) ψ, a cytoplasmic suppressor of super-suppression in yeast. Heredity 20:505–521CrossRefGoogle Scholar
  8. Crow ET, Li L (2011) Newly identified prions in budding yeast, and their possible functions. Semin Cell Dev Biol 5:452–459Google Scholar
  9. Crick F (1984) Memory and molecular turnover. Nature 312:101PubMedCrossRefGoogle Scholar
  10. Du Z, Park KW, Yu H, Fan Q, Li L (2008) Newly identified prion linked to the chromatin remodeling factor Swi1 in Saccharomyces cerevisiae. Nat Genet 40:460–465PubMedCrossRefGoogle Scholar
  11. Derkatch IL, Chernoff YO, Kushnirov VV, Inge-Vechtomov SG, Liebman SW (1996) Genesis and variability of ψ prion factors in Saccharomyces cerevisiae. Genetics 144(4):1375–1386PubMedGoogle Scholar
  12. Dudek SM, Fields RD (2002) Somatic action potentials are sufficient for late-phase LTP-related cell signaling. Proc Natl Acad Sci USA 99:3962–3967PubMedCrossRefGoogle Scholar
  13. Eaglestone SS, Cox BS, Tuite MF (1999) Translation termination efficiency can be regulated in Saccharomyces cerevisiae by environmental stress through a prion-mediated mechanism. EMBO J 18:1974–1981CrossRefGoogle Scholar
  14. Fiumara F, Fioriti L, Kandel ER, Hendrickson WA (2010) Essential role of coiled coils for aggregation and activity of Q/N-rich prions and PolyQ proteins. Cell 143(7):1121–1135PubMedCrossRefGoogle Scholar
  15. Frey U, Morris RG (1997) Synaptic tagging and long-term potentiation. Nature 385:533–536PubMedCrossRefGoogle Scholar
  16. Frey U, Morris RG (1998) Weak before strong: dissociating synaptic tagging and plasticity-factor accounts of late-LTP. Neuropharmacology 37:545–552PubMedCrossRefGoogle Scholar
  17. Ganusova EE, Ozolins LN, Bhagat S, Newnam GP, Wegrzyn RD, Sherman MY, Chernoff YO (2006) Modulation of prion formation, aggregation, and toxicity by the actin cytoskeleton in yeast. Mol Cell Biol 26:617–629PubMedCrossRefGoogle Scholar
  18. Griffith JS (1967) Self-replication and scrapie. Nature 215:1043–1044PubMedCrossRefGoogle Scholar
  19. Groisman I, Jung MY, Sarkissian M, Cao Q, Richter JD (2002) Translational control of the embryonic cell cycle. Cell 109:473–483PubMedCrossRefGoogle Scholar
  20. Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S (2012) Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature 482(7385):363–368PubMedCrossRefGoogle Scholar
  21. Hou F, Sun L, Zheng H, Skaug B, Jiang QX, Chen ZJ (2011) MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146:448–461PubMedCrossRefGoogle Scholar
  22. Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1113–1120CrossRefGoogle Scholar
  23. Keleman K, Krüttner S, Alenius M, Dickson BJ (2007) Function of the Drosophila CPEB protein Orb2 in long-term courtship memory. Nat Neurosci 10:1587–1593PubMedCrossRefGoogle Scholar
  24. Lisman J, Malenka RC, Nicoll RA, Malinow R (1997) Learning mechanisms: the case for CaM-KII. Science 276:2001–2002PubMedCrossRefGoogle Scholar
  25. Majumdar A, Cesario WC, White-Grindley E, Jiang H, Ren F, Khan MR, Li L, Choi EM, Kannan K, Guo F, Unruh J, Slaughter B, Si K (2012) Critical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory. Cell 148:515–529PubMedCrossRefGoogle Scholar
  26. Martin KC, Casadio A, Zhu H, Yaping E, Rose JC, Chen M, Bailey CH, Kandel ER (1997) Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91:927–938PubMedCrossRefGoogle Scholar
  27. Mastushita-Sakai T, White-Grindley E, Samuelson J, Seidel C, Si K (2010) Drosophila Orb2 targets genes involved in neuronal growth, synapse formation, and protein turnover. Proc Natl Acad Sci USA 107:11987–11992PubMedCrossRefGoogle Scholar
  28. Mendez R, Murthy KG, Ryan K, Manley JL, Richter JD (2000) Phosphorylation of CPEB by Eg2 mediates the recruitment of CPSF into an active cytoplasmic polyadenylation complex. Mol Cell 2000:1253–1259CrossRefGoogle Scholar
  29. Miniaci MC, Kim JH, Puthanveettil SV, Si K, Zhu H, Kandel ER, Bailey CH (2008) Sustained CPEB-dependent local protein synthesis is required to stabilize synaptic growth for persistence of long-term facilitation in Aplysia. Neuron 59:1024–1036PubMedCrossRefGoogle Scholar
  30. Namy O, Galopier A, Martini C, Matsufuj S, Fabret C, Rousset JP (2008) Epigenetic control of polyamines by the prion [PSI(+)]. Nat Cell Biol 10:1069–1075PubMedCrossRefGoogle Scholar
  31. Patino MM, Liu JJ, Glover JR, Lindquist S (1996) Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 273:622–626PubMedCrossRefGoogle Scholar
  32. Paushkin SV, Kushnirov VV, Smirnov VN, Ter-Avanesyan MD (1996) Propagation of the yeast prion-like [psi+] determinant is mediated by oligomerization of the SUP35-encoded polypeptide chain release factor. EMBO J 15(12):3127–3134PubMedGoogle Scholar
  33. Pavlopoulos E, Trifilieff P, Chevaleyre V, Fioriti L, Zairis S, Pagano A, Malleret G, Kandel ER (2011) Neuralized1 activates CPEB3: a function of non-proteolytic ubiquitin in synaptic plasticity and memory storage. Cell 147:1369–1383PubMedCrossRefGoogle Scholar
  34. Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216:136–144PubMedCrossRefGoogle Scholar
  35. Puthanveettil S, Kandel ER (2011) Molecular mechanisms for the initiation and maintenance of long-term memory storage. In: Curran T, Christen Y (eds) Two faces of evil: cancer and neurodegeneration. Springer, New York, pp 143–160CrossRefGoogle Scholar
  36. Richter JD (1999) Cytoplasmic polyadenylation in development and beyond. Microbiol Mol Biol Rev 63:446–456PubMedGoogle Scholar
  37. Schroeder KE, Condic ML, Eisenberg LM, Yost HJ (1999) Spatially regulated translation in embryos: asymmetric expression of maternal Wnt-11 along the dorsal-ventral axis in Xenopus. Dev Biol 214:288–297PubMedCrossRefGoogle Scholar
  38. Shorter J, Lindquist S (2005) Prions as adaptive conduits of memory and inheritance. Nat Rev Genet 6:435–450PubMedCrossRefGoogle Scholar
  39. Si K, Giustetto M, Etkin A, Hsu R, Janisiewicz AM, Miniaci MC, Kim JH, Zhu H, Kandel ER (2003a) A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse specific long-term facilitation in aplysia. Cell 115:893–904PubMedCrossRefGoogle Scholar
  40. Si K, Lindquist S, Kandel ER (2003b) A neuronal isoform of the aplysia CPEB has prion-like properties. Cell 115:879–891PubMedCrossRefGoogle Scholar
  41. Si K, Choi YB, White-Grindley E, Majumdar A, Kandel ER (2010) Aplysia CPEB can form prion-like multimers in sensory neurons that contribute to long-term facilitation. Cell 140:421–435PubMedCrossRefGoogle Scholar
  42. Stebbins-Boaz B, Hake LE, Richter JD (1996) CPEB controls the cytoplasmic polyadenylation of cyclin, Cdk2 and c-mos mRNAs and is necessary for oocyte maturation in Xenopus. EMBO J 15:2582–2592PubMedGoogle Scholar
  43. Tan L, Chang JS, Costa A, Schedl P (2001) An autoregulatory feedback loop directs the localized expression of the Drosophila CPEB protein Orb in the developing oocyte. Development 128:1159–1169PubMedGoogle Scholar
  44. Theis M, Si K, Kandel ER (2003) 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(16):9602–9607PubMedCrossRefGoogle Scholar
  45. Thompson KR, Otis KO, Chen DY, Zhao Y, O’Dell TJ, Martin KC (2004) Synapse to nucleus signaling during long-term synaptic plasticity; a role for the classical active nuclear import pathway. Neuron 44:997–1009PubMedGoogle Scholar
  46. True HL, Lindquist SL (2000) A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407:477–483PubMedCrossRefGoogle Scholar
  47. True HL, Berlin I, Lindquist SL (2004) Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits. Nature 431:184–187PubMedCrossRefGoogle Scholar
  48. Wickner RB (1994) [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. Science 264:566–569PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Eric R. Kandel
    • 1
    Email author
  • Irina Derkatch
    • 1
  • Elias Pavlopoulos
    • 1
  1. 1.Center for Neurobiology and Behavior, Howard Hughes Medical InstituteColumbia UniversityNew YorkUSA

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