Amyloidogenic Oligomerization Transforms Drosophila Orb2 from a Translation Repressor to an Activator

Memories are thought to be formed in response to transient experiences, in part through changes in local protein synthesis at synapses. In Drosophila, the amyloidogenic (prion-like) state of the RNA binding protein Orb2 has been implicated in long-term memory, but how conformational conversion of Orb2 promotes memory formation is unclear. Combining in vitro and in vivo studies, we find that the monomeric form of Orb2 represses translation and removes mRNA poly(A) tails, while the oligomeric form enhances translation and elongates the poly(A) tails and imparts its translational state to the monomer. The CG13928 protein, which binds only to monomeric Orb2, promotes deadenylation, whereas the putative poly(A) binding protein CG4612 promotes oligomeric Orb2-dependent translation. Our data support a model in which monomeric Orb2 keeps target mRNA in a translationally dormant state and experience-dependent conversion to the amyloidogenic state activates translation, resulting in persistent alteration of synaptic activity and stabilization of memory. [Display omitted] •Drosophila Orb2 has two distinct physical states: monomer and amyloid-like oligomer•The monomeric Orb2 represses, whereas oligomeric Orb2 activates translation•The monomeric Orb2 removes, whereas oligomeric Orb2 protects/elongates poly(A) tail•Two proteins, CG13928 and CG4612, contribute to repression and activation, respectively The Orb2 protein switches from repressing to activating translation when it forms amyloid-like oligomers, suggesting a possible mechanism by which fleeting experiences create an enduring memory.