Investigating the prion formation of neuronal CPEB

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DESCRIPTION (provided by applicant): Prions are proteins that can switch to self-perpetuating, infectious conformations, a property shared by proteins across the evolutionary spectrum. Although prions and the amyloid fibers they form are usually linked to diseases that often result in neurodegeneration, it has been proposed that prions can also be beneficial to the cell with diverse normal biological functions including cell-adhesion, adaptation to environmental stresses, and skin pigmentation. With our collaborators (Drs. Eric Kandel, Columbia University, and Kausik Si, Stowers Institute), we postulate that due to the prion-like, self-templating nature of Aplysia neuronal CPEB (a translational activator of dormant mRNAs) alterations of a synapse that are key to learning and memory functions of the brain can be maintained long-term. Our aim is to characterize the amyloid nature of neuronal CPEB in order to generate mutants that cannot switch into the active prion conformation or that behave as dominant-negative versions of neuronal CPEB. These mutants will then be tested in vivo in yeast and higher organisms to investigate their effects on translational activation and ultimately synaptic plasticity. Public health interest: Prion proteins and the amyloid fibers they form are best known as causative agents of neurodegenerative diseases in humans. Recent studies showed, however, that certain prions might also be beneficial to the cell or carry out normal biological functions. In particular, the prion-like protein we study, nCPEB, might play a pivotal role in synapse maintenance. Ultimately, we would like to demonstrate that the molecular memory that is an intrinsic property of self-perpetuating prions may play a role in synaptic plasticity, learning and memory. It is therefore of great importance to study nCPEB, to both enhance our general understanding of prions that are detrimental to men, and gain new insights into beneficial functional aspects of prion biology. Given that there are so few amyloids for which we have even an elementary grasp of structure, the ability to take advantage of yeast genetic analysis in combination with biophysical techniques will position us to shed new light on the field of amyloid biology.