Editors' ChoiceNeuroscience

A pro-memory prion protein

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Sci. Signal.  07 Jul 2015:
Vol. 8, Issue 384, pp. ec181
DOI: 10.1126/scisignal.aac9389

Prion proteins aggregate in cells and are commonly associated with neurodegenerative disorders that are often marked by cognitive impairment. Memory formation and learning is mediated by synaptic plasticity, which requires localized translation at the synapses. Three studies reveal that prion-like aggregation of the translational regulatory protein CPEB3 (cytoplasmic polyadenylation element-binding protein 3) in neurons promotes long-term memory maintenance not only in invertebrates, but also in mice. Stephan et al. found that CPEB3 aggregated in cultured mouse neurons after glutamic acid stimulation. Deletion analysis and mass spectrometry in yeast complemented with coimmunoprecipitation assays in cultured neurons showed that CPEB3 bound to the actin cytoskeleton, an interaction that was essential for CPEB3 aggregation and its function in promoting the translation of mRNAs, including that of actin-encoding transcripts, indicating possible feedforward regulation. In the second study, Fioriti et al. characterized the role of CPEB3 in learning and memory. Stimulation of either cultured mouse hippocampal neurons with glutamate or glycine or hippocampal slices with dopamine increased the abundance of CPEB3. Furthermore, the abundance and aggregation of CPEB3 was higher in hippocampal extracts from mice subjected to water maze training or fear conditioning compared to those from naïve controls. Mice lacking CPEB3 specifically in the forebrain had impaired long-term potentiation in the hippocampus (a marker of synaptic plasticity) and long-term memory consolidation (learning) without changes in short-term memory or locomotion. Ablating CPEB3 after a learning trial in the water maze impaired memory recall in mice, suggesting that CPEB3 functions in both the formation and maintenance of long-term memory. Knockout mice also had decreased abundance of newly synthesized GluA1 and GluA2 (AMPA receptor subunits) after water maze training, indicating that activity-dependent translation of AMPA receptor-encoding mRNAs was impaired in the absence of CPEB3. Both Stephan et al. and Fioriti et al. showed that the activity of CPEB3 was dependent on an N-terminal region.

Despite the beneficial role of aggregated CPEB3 these studies suggest that unregulated protein aggregation is detrimental to cells. In a third study, Drisaldi et al. examined the biochemical regulation of CPEB3 aggregation and function. In lysates from mouse hippocampal neurons that were either unstimulated in culture or isolated from naïve mice, CPEB3 was SUMOylated. Glycine stimulation of cultured hippocampal neurons or fear conditioning in mice decreased the fraction of SUMOylated CPEB3 and increased CPEB3 aggregation. Overexpressing a chimeric CPEB3 fused to an uncleavable SUMO-2 moiety in glycine-treated hippocampal neurons prevented the aggregation and translational activity of CPEB3 and decreased filopodia formation, a morphological change that is associated with synaptic plasticity. The transcript encoding SUMO-2 was a target of CPEB3, and overexpression of SUMO-2 increased the SUMOylation of CPEB3 and inhibited its aggregation, suggesting that a negative feedback loop limits CPEB3 aggregation. Together, the studies uncover a mechanism underlying translation-mediated regulation of synaptic plasticity.

L. Fioriti, C. Myers, Y.-Y. Huang, X. Li, J. S. Stephan, P. Trifilieff, L. Colnaghi, S. Kosmidis, B. Drisaldi, E. Pavlopoulos, E. R. Kandel, The persistence of hippocampal-based memory requires protein synthesis mediated by the prion-like protein CPEB3. Neuron 86, 1433–1448 (2015). [PubMed]

B. Drisaldi, L. Colnaghi, L. Fioriti, N. Rao, C. Myers, A. M. Snyder, D. J. Metzger, J. Tarasoff, E. Konstantinov, P. E. Fraser, J .L. Manley, E. R. Kandel, SUMOylation is an inhibitory constraint that regulates the prion-like aggregation and activity of CPEB3. Cell Reports 11, 1694–1702 (2015). [PubMed]

J. S. Stephan, L. Fioriti, N. Lamba, L. Colnaghi, K. Karl, I. L. Derkatch, E. R. Kandel, The CPEB3 protein is a functional prion that interacts with the actin cytoskeleton. Cell Reports 11, 1772–1785 (2015). [PubMed]