Prions: What Are They Good For?

Si, Kausik

doi:10.1146/annurev-cellbio-100913-013409

Cited by 48 publications

(44 citation statements)

References 112 publications

(131 reference statements)

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“…That being stated, it is useful to outline key requirements for establishing a model, in order to have an objective yardstick for assessing the conclusiveness of current data, which have been discussed and/ or reviewed in recent articles. 9,10 (a) Synaptic activity that triggers long-term memory should be demonstrated to result in conformational switch of CPEB from a monomeric to oligomeric prion-like form at active but not at inactive synapses. (b) At the activated synapse, the new oligomeric CPEB should be capable of self-renewal, recruiting monomeric CPEB into oligomers over the extended period for which memory is retained.…”

Section: Characterization Of Prions and Prion Domainsmentioning

confidence: 99%

“…Such a model has been proposed and is supported by several observations of the prion-domain containing RNA regulatory protein CPEB. 9,10 This review will introduce diverse aspects of molecular biology of long-term memory, discuss the role of translational control mechanisms in long-term synaptic plasticity with a particular focus on the role and potential mechanisms by which prion-domain containing RNA-binding proteins enable longterm memory formation and retention.…”

Section: Introductionmentioning

confidence: 99%

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

Sudhakaran

Ramaswami

2016

RNA Biology

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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.

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Section: Characterization Of Prions and Prion Domainsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sudhakaran

Ramaswami

2016

RNA Biology

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“…The type of protein involved in this benign aggregation is known as a functional amyloid, or prion. Although it undergoes conformational changes and organized polymerization, it is an important player in many processes, such as memory consolidation (CPEB, CPEB3, and Orb2), the immune response to viral infection (mitochondrial antiviral signaling protein (MAVS)), and hormone transport (Pmel17) (7)(8)(9)(10). Yeast prions have such characteristics, and there are several important reviews on this subject (11,12).…”

mentioning

confidence: 99%

“…Several recent studies have expanded the prion-like amyloid aggregation research to cancer because of the aggregation of p53 and other tumor suppressors (6,(22)(23)(24). This correlation between misfolding/aggregation and nucleic acid binding is not restricted to pathological events and serves some routine functions, including the persistence of long-term memory, as in the case of CPEB in Aplysia and CPEB3 in mammals (10), as well as the amyloid-like aggregation of the RNA-binding protein Rim4, involved in gametogenesis (25). Recently, it was shown that several different amyloid fibrils induce the release of extracellular traps of chromatin from neutrophils (26).…”

mentioning

confidence: 99%

The “Jekyll and Hyde” Actions of Nucleic Acids on the Prion-like Aggregation of Proteins

Silva

Cordeiro

2016

Journal of Biological Chemistry

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Protein misfolding results in devastating degenerative diseases and cancer. Among the culprits involved in these illnesses are prions and prion-like proteins, which can propagate by converting normal proteins to the wrong conformation. For spongiform encephalopathies, a real prion can be transmitted among individuals. In other disorders, the bona fide prion characteristics are still under investigation. Besides inducing misfolding of native proteins, prions bind nucleic acids and other polyanions. Here, we discuss how nucleic acid binding might influence protein misfolding for both disease-related and benign, functional prions and why the line between bad and good amyloids might be more subtle than previously thought.

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“…Nucleic acid reactivity clearly depends on the protein assembly state and to some extent on the protein sequence. Based on the idea that the amyloid fold is ancient and may have co-evolved with RNAs [110,111], it is plausible to propose that such proteins present a general nucleic acid binding property resulting from this evolution process. NA-binding can thus result in ribonucleoprotein complexes that possess important cellular functions, for instance, being related to functional amyloids [112] or to amyloidogenic diseases [99].…”

Section: Discussionmentioning

confidence: 99%

Unraveling Prion Protein Interactions with Aptamers and Other PrP-Binding Nucleic Acids

Macedo

Cordeiro

2017

IJMS

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Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative disorders that affect humans and other mammals. The etiologic agents common to these diseases are misfolded conformations of the prion protein (PrP). The molecular mechanisms that trigger the structural conversion of the normal cellular PrP (PrPC) into the pathogenic conformer (PrPSc) are still poorly understood. It is proposed that a molecular cofactor would act as a catalyst, lowering the activation energy of the conversion process, therefore favoring the transition of PrPC to PrPSc. Several in vitro studies have described physical interactions between PrP and different classes of molecules, which might play a role in either PrP physiology or pathology. Among these molecules, nucleic acids (NAs) are highlighted as potential PrP molecular partners. In this context, the SELEX (Systematic Evolution of Ligands by Exponential Enrichment) methodology has proven extremely valuable to investigate PrP–NA interactions, due to its ability to select small nucleic acids, also termed aptamers, that bind PrP with high affinity and specificity. Aptamers are single-stranded DNA or RNA oligonucleotides that can be folded into a wide range of structures (from harpins to G-quadruplexes). They are selected from a nucleic acid pool containing a large number (1014–1016) of random sequences of the same size (~20–100 bases). Aptamers stand out because of their potential ability to bind with different affinities to distinct conformations of the same protein target. Therefore, the identification of high-affinity and selective PrP ligands may aid the development of new therapies and diagnostic tools for TSEs. This review will focus on the selection of aptamers targeted against either full-length or truncated forms of PrP, discussing the implications that result from interactions of PrP with NAs, and their potential advances in the studies of prions. We will also provide a critical evaluation, assuming the advantages and drawbacks of the SELEX (Systematic Evolution of Ligands by Exponential Enrichment) technique in the general field of amyloidogenic proteins.

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Prions: What Are They Good For?

Cited by 48 publications

References 112 publications

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

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

The “Jekyll and Hyde” Actions of Nucleic Acids on the Prion-like Aggregation of Proteins

Unraveling Prion Protein Interactions with Aptamers and Other PrP-Binding Nucleic Acids

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