The Prion‐like Cytoplasmic Polyadenylation Element Binding (CPEB) Protein: Can Protein Aggregations in Long‐term Memory Formation inform Memory Loss in Amyloid Associated Neurodegenerative Disease?
Authors: Kessler Eric , Kambhampati Lasya , Kill Gaby , Mackenzie Emersen , Meyer Mackenzie , Parthasarathy Madhu , Silwal Nirvan , Smuckler Hannah , Wang Jerry 
Published: April 2020

Proteinaceous infectious particles or prions are harmful misfolded proteins characterized by a self‐perpetuating amyloidogenic state. These infectious agents target the nervous system and result in rare conditions including Creutzfeldt‐Jacobs disease and kuru, bovine spongiform encephalopathy and scrapie, which are fatal in humans, and cattle and sheep, respectively. Prions have two distinct states: monomeric and amyloidogenic aggregated. The monomeric state is non‐pathogenic while the aggregated state can recruit other monomers into the pathogenic aggregated form. Though not caused by prions, a number of neurodegenerative disorders including Alzheimer’s, Huntington’s, and Parkinson’s disease are associated with the accumulation of misfolded amyloid forming proteins in the brain. In concert with the discoveries involving prions and amyloid‐associated disease, a reductionist approach using the Aplysia sea slug was being developed to study modifications of simple reflexes and underlying neural circuits in an effort to uncover the molecular basis of short‐term and long‐term memory. Through these studies it has been demonstrated that long‐term memory is a function of changes that occur within the synapses and requires synthesis of new proteins in the synapse. More recently, a protein, cytoplasmic polyadenylation element‐binding (CPEB). In contrast to prions, prion‐like proteins are regulated and are functional in their aggregated state. The Blue Valley North 2019–2020 SMART (Students Modeling A Research Topic) Team, supported by the CBM at MSOE, modeled the Apylsia CPEB protein using JMol and 3D printing technology with the goal of exploring this protein’s unique properties and its role in memory formation. In its monomeric state CPEB is inhibited by the microRNA miR22. In contrast, when stimulated by serotonin, a neurotransmitter that induces long‐term synaptic facilitation, miR22 is downregulated, releasing CPEB from its inhibition, and allowing it to enter is active aggregate forming self‐sustaining state. In this state, CPEB activates dormant mRNA located in the axon terminals undergoing long‐term facilitation. Structurally, CPEB contains a N‐terminal region rich in glutamine and asparagine residues, and a C‐terminal RNA binding domain. Neuronal protein homologs with similar N‐terminal regions exist in yeast, mice, and humans as well. It is hypothesized that the N‐terminal region forms both a b‐sheet and an a‐helical coiled coil which facilitate aggregation and the formation of central axis from which the aggregate’s separate RNA binding domains protrude. These open and accessible RNA binding platforms expedite mRNA activation. In this manner CPEB can coordinate the translation of a population of mRNAs important in long‐term memory formation. Though counterintuitive we are hopeful that further structural analysis of the CPEB protein involved in memory formation will inform our understanding of amyloid aggregates associated with memory loss in neurodegenerative disease.