scholarly journals Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

2018 ◽  
Vol 19 (8) ◽  
pp. 2280 ◽  
Author(s):  
Stylianos Ravanidis ◽  
Fedon-Giasin Kattan ◽  
Epaminondas Doxakis
Keyword(s):  
Associated Factors ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Muscular Atrophy ◽  
Fragile X ◽  
Autism Spectrum ◽  
Cytoplasmic Inclusions ◽  
Neuronal Homeostasis ◽  
Rnp Granules

The timing, dosage and location of gene expression are fundamental determinants of brain architectural complexity. In neurons, this is, primarily, achieved by specific sets of trans-acting RNA-binding proteins (RBPs) and their associated factors that bind to specific cis elements throughout the RNA sequence to regulate splicing, polyadenylation, stability, transport and localized translation at both axons and dendrites. Not surprisingly, misregulation of RBP expression or disruption of its function due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to the pathogenesis of several neuropsychiatric and neurodegenerative disorders such as fragile-X syndrome, autism spectrum disorders, spinal muscular atrophy, amyotrophic lateral sclerosis and frontotemporal dementia. This review discusses the roles of Pumilio, Staufen, IGF2BP, FMRP, Sam68, CPEB, NOVA, ELAVL, SMN, TDP43, FUS, TAF15, and TIA1/TIAR in RNA metabolism by analyzing their specific molecular and cellular function, the neurological symptoms associated with their perturbation, and their axodendritic transport/localization along with their target mRNAs as part of larger macromolecular complexes termed ribonucleoprotein (RNP) granules.

scholarly journals Proteostasis and RNA Binding Proteins in Synaptic Plasticity and in the Pathogenesis of Neuropsychiatric Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Matthew E. Klein ◽  
Hannah Monday ◽  
Bryen A. Jordan
Keyword(s):  
Synaptic Plasticity ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Neuronal Morphology ◽  
Synaptic Activity ◽  
Protein Abundance

Decades of research have demonstrated that rapid alterations in protein abundance are required for synaptic plasticity, a cellular correlate for learning and memory. Control of protein abundance, known as proteostasis, is achieved across a complex neuronal morphology that includes a tortuous axon as well as an extensive dendritic arbor supporting thousands of individual synaptic compartments. To regulate the spatiotemporal synthesis of proteins, neurons must efficiently coordinate the transport and metabolism of mRNAs. Among multiple levels of regulation, transacting RNA binding proteins (RBPs) control proteostasis by binding to mRNAs and mediating their transport and translation in response to synaptic activity. In addition to synthesis, protein degradation must be carefully balanced for optimal proteostasis, as deviations resulting in excess or insufficient abundance of key synaptic factors produce pathologies. As such, mutations in components of the proteasomal or translational machinery, including RBPs, have been linked to the pathogenesis of neurological disorders such as Fragile X Syndrome (FXS), Fragile X Tremor Ataxia Syndrome (FXTAS), and Autism Spectrum Disorders (ASD). In this review, we summarize recent scientific findings, highlight ongoing questions, and link basic molecular mechanisms to the pathogenesis of common neuropsychiatric disorders.

RNA-Binding Proteins and Translation in Neurodegenerative Disease

2020 ◽  
Author(s):  
Kent E. Duncan
Keyword(s):  
Neurodegenerative Diseases ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Potential Contribution ◽  
Fused In Sarcoma ◽  
Specific Mrnas ◽  
Ataxia Syndrome ◽  
Research Frontiers

Both RNA-binding proteins (RBPs) and translation are increasingly implicated in several neurodegenerative diseases, but their specific roles in promoting disease are not yet fully defined. This chapter critically evaluates the evidence that altered translation of specific mRNAs mediated by RNA-binding proteins plays an important role in driving specific neurodegenerative diseases. First, diseases are discussed where a causal role for RNA-binding proteins in disease appears solid, but whether this involves altered translation is less clear. The main foci here are TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Subsequently, diseases are presented where altered translation is believed to contribute, but involvement of RNA-binding proteins is less clear. These include Huntington’s and other repeat expansion disorders such as fragile X tremor/ataxia syndrome (FXTAS), where repeat-induced non-AUG-initiated (RAN) translation is a focus. The potential contribution of both canonical and non-canonical RBPs to altered translation in Parkinson’s disease is discussed. The chapter closes by proposing key research frontiers for the field to explore and outlining methodological advances that could help to address them.

scholarly journals Axonal localization of the fragile X family of RNA binding proteins is conserved across mammals

2019 ◽  
Vol 528 (3) ◽  
pp. 502-519 ◽  
Author(s):  
Katherine A. Shepard ◽  
Lulu I T. Korsak ◽  
Danielle DeBartolo ◽  
Michael R. Akins
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X

scholarly journals Molecular dynamics of FMRP and other RNA-binding proteins in MEG-01 differentiation: the role of mRNP complexes in non-neuronal development

2016 ◽  
Vol 94 (6) ◽  
pp. 597-608 ◽  
Author(s):  
M. McCoy ◽  
D. Poliquin-Duchesneau ◽  
F. Corbin
Keyword(s):  
Protein Content ◽  
Binding Proteins ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Morphological Changes ◽  
Fragile X ◽  
Cellular Protein ◽  
The Body ◽  
Total Protein Content

Asymmetrically differentiating cells are formed with the aid of RNA-binding proteins (RBPs), which can bind, stabilize, regulate, and transport target mRNAs. The loss of RBPs in neurons may lead to severe neurodevelopmental diseases such as the Fragile X Syndrome with the absence of the Fragile X Mental Retardation Protein (FMRP). Because the latter is ubiquitous and shares many similarities with other RBPs involved in the development of peripheral cells, we suggest that FMRP would have a role in the differentiation of all tissues where it is expressed. A MEG-01 differentiation model was, therefore, established to study the global developmental functions of FMRP. PMA induction of MEG-01 cells causes important morphological changes driven by cytoskeletal dynamics. Cytoskeleton change and colocalization analyses were performed by confocal microscopy and sucrose gradient fractionation. Total cellular protein content and de novo synthesis were also analyzed. Microtubular transport mediates the displacement of FMRP and other RBP-containing mRNP complexes towards regions of the cell in development. De novo protein synthesis decreases significantly upon differentiation and total protein content composition is altered. Because those results are comparable with those obtained in neurons, the absence of FMRP would have significant consequences in cells everywhere in the body. The latter should be further investigated to give a better understanding of the systemic implications of imbalances of FMRP and other functionally similar RBPs.

scholarly journals FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Raeann Goering ◽  
Laura I Hudish ◽  
Bryan B Guzman ◽  
Nisha Raj ◽  
Gary J Bassell ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Rna Localization ◽  
Null Mouse ◽  
Rna Sequences ◽  
Rna Molecules ◽  
G Quadruplex

The sorting of RNA molecules to subcellular locations facilitates the activity of spatially restricted processes. We have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these transcripts contain an enrichment of G-quadruplex sequences in their 3′ UTRs, suggesting that FMRP recognizes them to promote RNA localization. We observed similar results in neurons derived from Fragile X Syndrome patients. We identified the RGG domain of FMRP as important for binding G-quadruplexes and the transport of G-quadruplex-containing transcripts. Finally, we found that the translation and localization targets of FMRP were distinct and that an FMRP mutant that is unable to bind ribosomes still promoted localization of G-quadruplex-containing messages. This suggests that these two regulatory modes of FMRP may be functionally separated. These results provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

scholarly journals RNA-Binding Proteins hnRNP A2/B1 and CUGBP1 Suppress Fragile X CGG Premutation Repeat-Induced Neurodegeneration in a Drosophila Model of FXTAS

Neuron ◽  
2007 ◽  
Vol 55 (4) ◽  
pp. 565-571 ◽  
Author(s):  
Oyinkan A. Sofola ◽  
Peng Jin ◽  
Yunlong Qin ◽  
Ranhui Duan ◽  
Huijie Liu ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Drosophila Model

Molecular Functions of the Mammalian Fragile X Mental Retardation Protein: Insights Into Mental Retardation and Synaptic Plasticity

2013 ◽  
Author(s):  
Claudia Bagni ◽  
Eric Klann
Keyword(s):  
Mental Retardation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Rna Binding Protein ◽  
Fragile X Mental Retardation ◽  
The Family ◽  
Mental Retardation Protein ◽  
The Brain

Chapter 8 discusses how Fragile X syndrome (FXS) is caused by the absence of the RNA-binding protein fragile X mental retardation protein (FMRP). FMRP is highly expressed in the brain and gonads, the two organs mainly affected in patients with the syndrome. Functionally, FMRP belongs to the family of RNA-binding proteins, shuttling from the nucleus to the cytoplasm, and, as shown for other RNA-binding proteins, forms large messenger ribonucleoparticles.

scholarly journals Axonal Transport and Local Translation of mRNA in Neurodegenerative Diseases

2021 ◽  
Vol 14 ◽  
Author(s):  
Seiichi Nagano ◽  
Toshiyuki Araki
Keyword(s):  
Neurodegenerative Diseases ◽  
Axonal Transport ◽  
Rna Binding ◽  
Synapse Formation ◽  
Rna Binding Proteins ◽  
Muscular Atrophy ◽  
Fragile X ◽  
Local Translation ◽  
Axon Elongation ◽  
And Function

Since neurons have long neurites including axons, it is crucial for the axons to transport many intracellular substances such as proteins and mitochondria in order to maintain their morphology and function. In addition, mRNAs have also been shown to be transported within axons. RNA-binding proteins form complexes with mRNAs, and regulate transport of the mRNAs to axons, as well as locally translate them into proteins. Local translation of mRNAs actively occurs during the development and damage of neurons, and plays an important role in axon elongation, regeneration, and synapse formation. In recent years, it has been reported that impaired axonal transport and local translation of mRNAs may be involved in the pathogenesis of some neurodegenerative diseases. In this review, we discuss the significance of mRNA axonal transport and their local translation in amyotrophic lateral sclerosis/frontotemporal dementia, spinal muscular atrophy, Alzheimer’s disease, and fragile X syndrome.

scholarly journals An Emerging Role for Post-translational Modifications in Regulating RNP Condensates in the Germ Line

2021 ◽  
Vol 8 ◽  
Author(s):  
Jennifer A. Schisa ◽  
Mohamed T. Elaswad
Keyword(s):  
Phase Separation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Germ Line ◽  
Rna Binding Proteins ◽  
Model Systems ◽  
Subsequent Formation ◽  
Post Translational Modifications ◽  
Rnp Granules

RNA-binding proteins undergo regulated phase transitions in an array of cell types. The phase separation of RNA-binding proteins, and subsequent formation of RNP condensates or granules, occurs during physiological conditions and can also be induced by stress. Some RNP granules have roles in post-transcriptionally regulating mRNAs, and mutations that prevent the condensation of RNA-binding proteins can reduce an organism’s fitness. The reversible and multivalent interactions among RNP granule components can result in RNP complexes that transition among diffuse and condensed states, the latter of which can be pathological; for example, in neurons solid RNP aggregates contribute to disease states such as amyotrophic lateral sclerosis (ALS), and the dysregulation of RNP granules in human germ cells may be involved in Fragile X-associated primary ovarian insufficiency. Thus, regulating the assembly of mRNAs and RNA-binding proteins into discrete granules appears to provide important functions at both cellular and physiological levels. Here we review our current understanding of the role of post-translational modifications (PTMs) in regulating the condensation of RNA-binding proteins in the germ line. We compare and contrast the in vitro evidence that methylation inhibits phase separation of RNA binding proteins, with the extent to which these results apply to the in vivo germ line environment of several model systems. We also focus on the role of phosphorylation in modulating the dynamics of RNP granules in the germ line. Finally, we consider the gaps that exist in our understanding of the role of PTMs in regulating germ line RNP granules.

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