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dc.contributor.advisorSi, Kausik
dc.contributor.authorKhan, Mohammed Repon
dc.description.abstractHow a transient experience creates a persistent memory remains a fundamental unresolved issue in neuroscience. One of the molecular processes that is believed to be critical for long- lasting memory is synthesis of new protein at the synapse. However, how synaptic protein synthesis is regulated and how these new proteins confers persistence of memory is largely unknown. Previous studies in Drosophila and Aplysia have implicated that a family of mRNA binding proteins known as Cytoplasmic Polyadenylation Element (CPE) binding proteins is essential for persistent change in experience-dependent synaptic efficacy and persistence of memory. Moreover specific CPEB family members demonstrate biophysical properties that are associated with prion-like proteins. They exist in two distinct physical states: a monomeric and a dominant self-sustaining amyloidogenic aggregated state. This suggested a model in which a transient experience creates persistence molecular alteration in the nervous system via recruiting a stable and self-sustaining amyloidogenic aggregates of neuronal CPEB. The primary objective of this thesis is to determine how Drosophila neuronal CPEB, Orb2, regulates protein synthesis and how conversion to the aggregated state effects its function. Combining in vitro and in vivo studies we find that the monomeric Orb2 represses, while the amyloidogenic oligomeric Orb2 enhances translation and imparts its translational state onto the monomer. The monomer removes, whereas the oligomer stabilizes and elongates the polyA tail of mRNA. In support of these findings, we have identified a two novel proteins: CG13928, which binds only to monomeric Orb2, promotes deadenylation, and CG4612, a putative polyA binding protein, promotes oligomeric Orb2-dependent translation. We posit that monomeric Orb2 keeps target mRNA in a translationally dormant state and experience-dependent conversion of Orb2 to the stable amyloidogenic state activates translation, resulting in persistent alteration of synaptic activity and stabilization of memory. This study also provides an example of an amyloid-based protein switch that turns a repressor into an activator.
dc.format.extent125 pages
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectLong term memory
dc.titleRole of Drosophila Orb2 (CPEB) in Synaptic Protein Synthesis
dc.contributor.cmtememberLeVine, Steven M
dc.contributor.cmtememberWright, Douglas E
dc.contributor.cmtememberZeitlinger, Julia
dc.contributor.cmtememberLi, Linheng
dc.contributor.cmtememberConaway, Ron
dc.thesis.degreeDisciplineMolecular & Integrative Physiology

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