Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Abstract

Long-term and short-term memories differ primarily in the duration of their retention. At a molecular level, long-term memory (LTM) is distinguished from short-term memory (STM) by its requirement for new gene expression. In addition to transcription (nuclear gene expression) the translation of stored mRNAs is necessary for LTM formation. The mechanisms and functions for temporal and spatial regulation of mRNAs required for LTM is a major contemporary problem, of interest from molecular, cell biological, neurobiological and clinical perspectives. This review discusses primary evidence in support for translational regulatory events involved in LTM and a model in which different phases of translation underlie distinct phases of consolidation of memories. However, it focuses largely on mechanisms of memory persistence and the role of prion-like domains in this defining aspect of long-term memory. We consider primary evidence for the concept that Cytoplasmic Polyadenylation Element Binding (CPEB) protein enables the persistence of formed memories by transforming in prion-like manner from a soluble monomeric state to a self-perpetuating and persistent polymeric translationally active state required for maintaining persistent synaptic plasticity. We further discuss prion-like domains prevalent on several other RNA-binding proteins involved in neuronal translational control underlying LTM. Growing evidence indicates that such RNA regulatory proteins are components of mRNP (RiboNucleoProtein) granules. In these proteins, prion-like domains, being intrinsically disordered, could mediate weak transient interactions that allow the assembly of RNP granules, a source of silenced mRNAs whose translation is necessary for LTM. We consider the structural bases for RNA granules formation as well as functions of disordered domains and discuss how these complicate the interpretation of existing experimental data relevant to general mechanisms by which prion-domain containing RBPs function in synapse specific plasticity underlying LTM.

Neuronal ribonucleoprotein granules: Dynamic sensors of localized signals

“…Repeated KCl stimuli, for example, induce a structural rearrangement of dendritically localized granules manifested by an increased partitioning of distinct RBPs (eg, FMRP and TDP‐43) into common granules . Furthermore, long‐term self‐sustaining changes in the conformational state of granule‐associated RBPs were shown to be induced by repeated cycles of neuronal stimulation . Interestingly in this case, persistent conformational changes were proposed to underlie synaptic tagging, a process that selectively marks activated synapses and restricts the competence to undergo long‐lasting changes to these synapses …”

Protein assembly systems in natural and synthetic biology

“…But in part due to the development of new techniques to study protein aggregates ( Table 2), we are gaining a new appreciation and understanding of their non-pathological roles. Protein aggregates play positive functions in a variety of cellular processes, including gene regulation [126,127], signaling [76,128,129], memory storage [56,130,131], DNA repair [132], cell fate decisions [130,[133][134][135], and even evolution [2]. These examples should serve as inspiration for synthetic biologists aiming to purposefully manipulate information flow in living systems ( Fig.…”

Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity

“…One clue might come from the recent studies on the consolidation of long-term memory for both yeast and mammals (Shorter and Lindquist 2005;Rayman and Kandel 2017;Sudhakaran and Ramaswami 2017). It has been well established that, at a molecular level, long-term memory is characterized by its requirement for changing the profiles of gene expression which is mainly implemented by the RNA-binding proteins with the prion-like domains (Shorter and Lindquist 2005;Rayman and Kandel 2017;Sudhakaran and Ramaswami 2017). However, even in the human genome, it is likely that there exist <240 RNA-binding proteins with the prion-like domains (Harrison and Shorter 2017).…”