How amyloid can be a substrate of memory: Formation of memories requires changes in the molecular composition of the synapse. How these changes occur and what maintains this altered synaptic composition so that memory can persist are unknown. Hervas et al. report the structure of a synaptic translation regulator called Orb2 isolated from the brains of adult fruit flies that is important for the maintenance and recall of memory. Orb2 forms an amyloid and changes its activity from a translation repressor to an activator. The amyloid core is composed of polar hydrophilic residues, as opposed to the hydrophobic ones found in nonfunctional or pathological amyloids. The structure provides insights into how amyloids could be a stable yet malleable substrate of memory. Science , this issue p. 1230

Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.

Background: Amyloids are ordered, insoluble protein aggregates, characterized by a cross-β sheet quaternary structure in which molecules in a β-strand conformation are stacked along the filament axis via intermolecular interactions. While amyloids are typically associated with pathological conditions, functional amyloids have also been identified and are present in a wide variety of organisms ranging from bacteria to humans. The cytoplasmic polyadenylation element-binding (CPEB) prion-like protein is an mRNA-binding translation regulator, whose neuronal isoforms undergo activity-dependent aggregation, a process that has emerged as a plausible biochemical substrate for memory maintenance. CPEB aggregation is driven by prion-like domains (PLD) that are divergent in sequence across species, and it remains unknown whether such divergent PLDs follow a similar aggregating assembly pathway. Here, we describe the amyloid-like features of the neuronalAplysiaCPEB (ApCPEB) PLD and compare them to those of theDrosophilaortholog, Orb2 PLD.Results: Using in vitro single-molecule and bulk biophysical methods, we find transient oligomers and mature amyloid-like filaments that suggest similarities in the late stages of the assembly pathway for both ApCPEB and Orb2 PLDs. However, while prior to aggregation the Orb2 PLD monomer remains mainly as a random coil in solution, ApCPEB PLD adopts a diversity of conformations comprising α-helical structures that evolve to coiled-coil species, indicating structural differences at the beginning of their amyloid assembly pathways.Conclusion: Our results indicate that divergent PLDs of CPEB proteins from different species retain the ability to form a generic amyloid-like fold through different assembly mechanisms.

The cytoplasmic polyadenylation element-binding protein 3 (CPEB3), is an RNA-binding protein which in its soluble state is localized in membraneless neuronal RNA granules keeping target mRNAs in a repressed state. The stimulus-dependent aggregation of CPEB3 activates target mRNAs translation, a central event for the maintenance of long-term memory-related synaptic plasticity in mammals. To date, the molecular determinants that govern both connected events remain unclear. Here, to gain insight into these processes, the biophysical properties of the human CPEB3 (hCPEB3) are characterized. We found that hCPEB3 homotypic condensation is mainly driven by hydrophobic interactions and occurs under physiological conditions. Moreover, hCPEB3 biomolecular condensates are dynamic inside living cells, whose localization and stabilization are mediated by its RNA-recognition domains. In contrast, the hCPEB3 polar N-terminal region is crucial for hCPEB3 amyloid-like aggregation in vitro , which is disrupted by the polyglutamine binding peptide 1 (QBP1), A β ₄₂ seeds and Hsp70, highlighting the importance of the Q ₄ RQ ₄ tract as well as the hydrophobic residues for hCPEB3 functional aggregation. Based on these findings, we postulate a model for hCPEB3’s role in memory persistence that advances a rather sophisticated control for hCPEB3 condensate dissociation and amyloid-like formation to achieve its physiological function. Highlights: hCPEB3 forms toxic intermediates that persist longer than in other functional amyloids. RNA-recognition domains stabilize hCPEB3 granule formation and dynamics. Different segments within hCPEB3 promote amyloidogenesis and liquid demixing. hCPEB3 amyloid formation requires both hydrophobic and polyQ segments. Graphical

Understanding early amyloidogenesis is key to rationally develop therapeutic strategies. Tau protein forms well‐characterized pathological deposits but its aggregation mechanism is still poorly understood. Using single‐molecule force spectroscopy based on a mechanical protection strategy, we studied the conformational landscape of the monomeric tau repeat domain (tau‐RD_244‐368). We found two sets of conformational states, whose frequency is influenced by mutations and the chemical context. While pathological mutations Δ280K and P301L and a pro‐amyloidogenic milieu favored expanded conformations and destabilized local structures, an anti‐amyloidogenic environment promoted a compact ensemble, including a conformer whose topology might mask two amyloidogenic segments. Our results reveal that to initiate aggregation, monomeric tau‐RD_244‐368 decreases its polymorphism adopting expanded conformations. This could account for the distinct structures found in vitro and across tauopathies.