Abstract
Amyloids are ordered protein aggregates that are typically associated with neurodegenerative diseases and cognitive impairment. By contrast, the amyloid-like state of the neuronal RNA binding protein Orb2 in Drosophila was recently implicated in memory consolidation, but it remains unclear what features of this functional amyloid-like protein give rise to such diametrically opposed behaviour. Here, using an array of biophysical, cell biological and behavioural assays we have characterized the structural features of Orb2 from the monomer to the amyloid state. Surprisingly, we find that Orb2 shares many structural traits with pathological amyloids, including the intermediate toxic oligomeric species, which can be sequestered in vivo in hetero-oligomers by pathological amyloids. However, unlike pathological amyloids, Orb2 rapidly forms amyloids and its toxic intermediates are extremely transient, indicating that kinetic parameters differentiate this functional amyloid from pathological amyloids. We also observed that a well-known anti-amyloidogenic peptide interferes with long-term memory in Drosophila. These results provide structural insights into how the amyloid-like state of the Orb2 protein can stabilize memory and be nontoxic. They also provide insight into how amyloid-based diseases may affect memory processes.
Highlights
Amyloids, whose cross-β fold has been postulated as the ancestral protein fold [1,2], were initially associated with fatal neurodegenerative disorders [3,4]
Amyloids are ordered protein aggregates typically associated with neurodegenerative diseases, such as Alzheimer disease and Parkinson disease, which usually result in cognitive impairment
Both recombinant Orb2A and Orb2B bind to thioflavin T (ThT) and Congo red (CR) dyes (Fig 1A– 1C and S1A Fig), and this binding is inhibited by amyloid destabilizing reagents such as rottlerin [23] or the polyphenol (-)-epigallocatechin gallate (EGCG: S1B Fig) [24,25]
Summary
Amyloids, whose cross-β fold has been postulated as the ancestral protein fold [1,2], were initially associated with fatal neurodegenerative disorders [3,4]. The discovery of functional amyloids raises the question of what causes such a strikingly distinct behaviour to that observed in pathological amyloids. It remains unclear what features are shared by functional and pathological amyloids and what determines whether a particular amyloid is functional rather than toxic. The Nterminus of some CPEB isoforms in Aplysia, Drosophila, and mouse have features characteristic of self-sustaining amyloidogenic (prion-like) proteins [9,10,11,12,13]. The neuronal specific isoform of Aplysia CPEB (ApCPEB) has a glutamine-asparagine (Q/N)-rich N-terminal domain, which resembles a yeast prion-like domain (PLD) [14], and it is predicted to have conformational flexibility [10]. It has been postulated that the switch to the oligomeric and self-perpetuating state contributes to the long-term maintenance of synapse-specific changes [16], providing a molecular mechanism for the persistence of memory [10]
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