How a transient experience produces a persistent memory is a fundamental, yet unsolved question. The substrate of memory has been broadly explored at the neuronal network level, establishing the synapse as the basic unit
How a transient experience produces a persistent memory is a fundamental, yet unsolved question. The substrate of memory has been broadly explored at the neuronal network level, establishing the synapse as the basic unit of memory. The encoding of a new memory involves persistent changes in the number and shape of synapses, however, the molecules and/or protein conformational states involved in persistent synaptic changes are largely unknown. Among such processes, the experience-dependent aggregation of a synaptic prion-like protein, the cytoplasmic polyadenylation element-binding (CPEB)/Orb2 protein, to a translationally active aggregated state has raised as a physical substrate of long-lasting memories across species. Using single-particle electron cryo-microscopy, along with in vitro functional assays, we reported the structure and biochemical activity of aggregated Orb2, isolated from 3 to 7-day-old Drosophila brains. This research revealed that Orb2 attains a hydrophilic amyloid state which enhances the translation of synaptic mRNA targets involved in memory persistence. Now, we are poised to use this knowledge for studying the molecular bases of forgetting. In Drosophila, aged flies show memory decline. However, it is unknown whether this phenomenon is Orb2-dependent. As the hydrophilic Orb2 amyloid is amenable to modification under specific environments, we hypothesize that during ageing, changes in Orb2 amyloid structure and/or conformation could lead to the formation of a translationally inactive amyloid state. To investigate and connect this hypothesis with age-related memory decline, we are developing a multidisciplinary project exploring the functional and atomic-level structural details of aggregated Orb2 isolated from the Drosophila brain during ageing. The knowledge obtained will offer insight into the bases of forgetting and into what traits make Orb2 amyloid functional, contrary to pathogenic ones linked to memory decline.
Fecha del seminario: 23/02/2022 12:00
Lugar del seminario: Seminario online
Ponente del seminario: Rubén Hervás
