Prions are proteins that promote the conversion of proteins of the same type to an alternate conformational state; typically, there is a soluble conformation and an insoluble, aggregating conformation. Furthermore, the state of the protein is heritable in an epigenetic manner. In humans, a prion protein is responsible for transmissible spongiform encephalopathies; however, in yeast, prions are not pathogenic and represent a mechanism of epigenetic regulation of protein activity. Si et al. noted that the model organism Aplysia, which is used for studying neurobiological questions such as the mechanisms underlying synaptic plasticity, expressed a neuronal form of the translational regulatory protein cytoplasmic polyadenylation element binding protein (CPEB) that had an N-terminal domain enriched in glutamine and asparagine residues, like that of other prion proteins. When tested in several yeast assays for prion activity (the ability to promote heritable conformational changes in the heterologously expressed protein or proteins to which the N-terminal domain was fused), the Aplysia CPEB behaved as though it were a prion. Surprisingly, the aggregated state of CPEB appeared to be the active form of the protein, at least in the yeast assays, which is in contrast to yeast prion proteins that are inactivated when they aggregate. Analysis of the role of Aplysia CPEB in response to prolonged exposure to or a short pulse of serotonin indicated that CPEB protein increases in a posttranscriptional manner. Furthermore, serotonin-stimulated synthesis of CPEB occurred in isolated neurites that had been detached from the cell bodies. Treatment of cells or processes with antisense oligonucleotides to disrupt CPEB expression resulted in no loss of the initial facilitation response, but impairment of the maintenance of the enhanced synaptic efficacy. Pharmacologic analysis indicated that CPEB stimulation required phosphoinositide 3-kinase but did not require protein kinase A or protein kinase C. What remains to be determined is whether CPEB behaves as a prion in Aplysia and whether changes in the protein's conformation occur in response to synaptic activity associated with long-term potentiation (see Darnell for discussion).
K. Si, S. Lindquist, E. R. Kandel, A neuronal isoform of the Aplysia CPEB has prion-like properties. Cell 115, 879-891 (2003). [Online Journal]
K. Si, M. Giustetto, A. Etkin, R. Hsu, A. M. Janisiewicz, M. C. Miniaci, J.-H. Kim, H. Zhu, E. R. Kandel, A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in Aplysia. Cell 115, 893-904 (2003). [Online Journal]
R. B. Darnell, Memory, synaptic transmission, and ... prions? Cell 115, 767-768 (2003). [Online Journal]