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

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.

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

Biochemistry and Cell Biology ◽

10.1139/bcb-2015-0131 ◽

2016 ◽

Vol 94 (6) ◽

pp. 597-608 ◽

Cited By ~ 1

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.

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

eLife ◽

10.7554/elife.52621 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 6

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.

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Fragile X mental retardation protein: A paradigm for translational control by RNA-binding proteins

Biochimie ◽

10.1016/j.biochi.2015.02.005 ◽

2015 ◽

Vol 114 ◽

pp. 147-154 ◽

Cited By ~ 32

Author(s):

Eileen Chen ◽

Simpson Joseph

Keyword(s):

Mental Retardation ◽

Translational Control ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Fragile X ◽

Protein A ◽

Fragile X Mental Retardation ◽

Mental Retardation Protein

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

Neuron ◽

10.1016/j.neuron.2007.07.021 ◽

2007 ◽

Vol 55 (4) ◽

pp. 565-571 ◽

Cited By ~ 215

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

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

10.1093/med/9780199744312.003.0008 ◽

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.

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

Neural Plasticity ◽

10.1155/2016/3857934 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 17

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.

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Biology of the fragile X mental retardation protein, an RNA-binding protein

Biochemistry and Cell Biology ◽

10.1139/o99-035 ◽

1999 ◽

Vol 77 (4) ◽

pp. 331-342 ◽

Cited By ~ 36

Author(s):

Edouard W Khandjian

Keyword(s):

Mental Retardation ◽

Binding Proteins ◽

Rna Binding ◽

Trinucleotide Repeat ◽

Rna Binding Proteins ◽

Cpg Island ◽

Fragile X ◽

Expression Patterns ◽

Fmr1 Gene ◽

Nucleocytoplasmic Trafficking

The fragile X syndrome, an X-linked disease, is the most frequent cause of inherited mental retardation. The syndrome results from the absence of expression of the FMR1 gene (fragile mental retardation 1) owing to the expansion of a CGG trinucleotide repeat located in the 5prime untranslated region of the gene and the subsequent methylation of its CpG island. The FMR1 gene product (FMRP) is a cytoplasmic protein that contains two KH domains and one RGG box, characteristics of RNA-binding proteins. FMRP is associated with mRNP complexes containing poly(A)+mRNA within actively translating polyribosomes and contains nuclear localization and export signals making it a putative transporter (chaperone) of mRNA from the nucleus to the cytoplasm. FMRP is the archetype of a novel family of cytoplasmic RNA-binding proteins that includes FXR1P and FXR2P. Both of these proteins are very similar in overall structure to FMRP and are also associated with cytoplasmic mRNPs. Members of the FMR family are widely expressed in mouse and human tissues, albeit at various levels, and seem to play a subtle choreography of expression. FMRP is most abundant in neurons and is absent in muscle. FXR1P is strongly expressed in muscle and low levels are detected in neurons. The complex expression patterns of the FMR1 gene family in different cells and tissues suggest that independent, however similar, functions for each of the three FMR-related proteins might be expected in the selection and metabolism of tissue-specific classes of mRNA. The molecular mechanisms altered in cells lacking FMRP still remain to be elucidated as well as the putative role(s) of FXR1P and FXR2P as compensatory molecules.Key words: RNA-binding proteins, polyribosomes, messenger ribonucleoprotein, messenger ribonucleoparticles, nucleocytoplasmic trafficking, mental retardation.

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FMRP association with and regulation of Fragile X granules exhibit circuit-dependent requirements for the KH2 RNA binding domain

10.1101/462168 ◽

2018 ◽

Author(s):

Ellen C. Gingrich ◽

Katherine A. Shepard ◽

Molly E. Mitchell ◽

Kirsty Sawicka ◽

Jennifer C. Darnell ◽

...

Keyword(s):

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Fragile X ◽

Brain Regions ◽

Binding Domain ◽

Cell Type ◽

Related Disorder ◽

Rna Granules ◽

Rna Binding Domain

AbstractThe localization and translation of mRNAs is controlled by a diverse array of ribonucleoprotein particles (RNPs), multimolecular complexes containing mRNAs and RNA binding proteins. Fragile X granules (FXGs) are a family of RNPs that exemplify the diversity of RNA granules in the mammalian nervous system. FXGs are found in a conserved subset of neurons, where they localize exclusively to the axonal compartment. Notably, the specific RNA binding proteins and mRNAs found in FXGs depend on brain circuit and neuron type, with all forebrain FXGs containing Fragile X mental retardation protein (FMRP), the protein mutated in the human autism-related disorder Fragile X syndrome. FMRP negatively regulates FXG abundance but is not required for their association with ribosomes or mRNA. To better understand the circuit-dependent mechanisms whereby FMRP associates with and regulates FXGs, we asked how a disease-causing point mutation, I304N, in the KH2 RNA binding domain of FMRP affects these granules in two brain regions – cortex and hippocampus. We found that FMRPI304N had a reduced association with FXGs, as it was absent from approximately half of FXGs in cortex and nearly all FXGs in hippocampus. FXG abundance correlated with the number of FMRP-containing FXGs, suggesting that FMRP regulates FXG abundance by KH2-independent mechanisms that occur locally within the granules. Together, these findings illustrate that cell type-dependent mechanisms guide the assembly of similar RNA granules. Further, point mutations in RNA granule components may lead to cell type-dependent phenotypes that produce atypical forms of disorders that normally arise from more severe mutations.

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Axonal localization of the Fragile X family of RNA binding proteins is conserved across mammals

10.1101/464552 ◽

2018 ◽

Author(s):

Katherine A. Shepard ◽

Lulu I T. Korsak ◽

Michael R. Akins

Keyword(s):

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Fragile X ◽

Mossy Fibers ◽

Developmental Expression ◽

Divergent Evolution ◽

Mammalian Brain ◽

Local Translation ◽

Related Family

AbstractSpatial segregation of proteins to neuronal axons arises in part from local translation of select mRNAs that are first transported into axons in ribonucleoprotein particles (RNPs), complexes containing mRNAs and RNA binding proteins. Understanding the importance of local translation for a particular circuit requires not only identifying axonal RNPs and their mRNA cargoes, but also whether these RNPs are broadly conserved or restricted to only a few species. Fragile X granules (FXGs) are axonal RNPs containing the Fragile X related family of RNA binding proteins along with ribosomes and specific mRNAs. FXGs were previously identified in mouse, rat, and human brains in a conserved subset of neuronal circuits but with species-dependent developmental profiles. Here we asked whether FXGs are a broadly conserved feature of the mammalian brain and sought to better understand the species-dependent developmental expression pattern. We found FXGs in a conserved subset of neurons and circuits in the brains of every examined species that together include mammalian taxa separated by up to 160 million years of divergent evolution. A developmental analysis of rodents revealed that FXG expression in frontal cortex and olfactory bulb followed consistent patterns in all species examined. In contrast, FXGs in hippocampal mossy fibers showed an increase in abundance across development for most species except for guinea pigs and members of the Mus genus, animals that navigate particularly small home ranges in the wild. The widespread conservation of FXGs suggests that axonal translation is an ancient, conserved mechanism for regulating the proteome of mammalian axons.

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