G quadruplex RNA structures in PSD-95 mRNA: potential regulators of miR-125a seed binding site accessibility

Stefanovic, Snezana; Bassell, Gary J.; Mihailescu, Mihaela‐Rita

doi:10.1261/rna.046722.114

Cited by 49 publications

(83 citation statements)

References 40 publications

(55 reference statements)

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“…In the former case, the long 5 ′ UTR expansion forms a CpG island, resulting in transcriptional silencing and therefore reduced levels of FMRP. Supporting the significance of the G-Qs, FMRP is capable of binding transcripts containing them (Darnell et al 2001;Vasilyev et al 2015), which can facilitate their translocation, in some cases, to synapses (Zhang et al 2014;Stefanovic et al 2015). In FXTAS patients, FMR1 is not completely silenced, and the expansion is actively transcribed into a repeat-containing RNA that has been reported to bind multiple RBPs, such as hnRNP A2/B1, MBNL1 (Iwahashi et al 2006), Sam68 (Sellier et al 2010), Drosha, DGCR8 (Sellier et al 2013), and more (Galloway and Nelson 2009).…”

Section: Rna-centric Mechanisms In C9orf72 Als-ftdmentioning

confidence: 97%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

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Section: Rna-centric Mechanisms In C9orf72 Als-ftdmentioning

confidence: 97%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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“…According to the mGluR scenario (Bear et al, 2004), the neighboring spines would undergo rapid PP2A-, FMRP-mediated de-repression of local translation. This in turn will increase the abundance of regulatory proteins such as Arc, CaMKIIα, PSD95, and CaMKIIβ (Darnell et al, 2011; Muddashetty et al, 2011; Niere et al, 2012; Park et al, 2008; Stefanovic et al, 2015), setting up the spine for a binary decision, to undergo LTD or LTP.…”

Section: Dysfunction Of Local Mrna Translation and Synaptic Plasticitymentioning

confidence: 99%

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

Mullins

Fishell

Tsien

2016

Neuron

163

166

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Understanding the mechanisms underlying autism spectrum disorders (ASD) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops, and provide detailed commentary for exemplar genes within each module.

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“…More recently, interactions between FMRP and RISC/ miRNAs have been shown to regulate dendritic protein synthesis and spine morphology [79,85]. It will be interesting if future studies show that FMRP interactions with Gquadruplexes provide a common mechanism to regulate miRNA seed site accessibility [91]. The tight association of phosphorylated FMRP with RISC/miRNAs may promote translational repression, whereas dephosphorylation of FMRP in response to activation of mGlu1/5 receptor results in release of miRISC and concomitant activation of translation [79].…”

Section: Fmrp Interactions With the Microrna Pathwaymentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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G quadruplex RNA structures in PSD-95 mRNA: potential regulators of miR-125a seed binding site accessibility

Cited by 49 publications

References 40 publications

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

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