<scp>DDX</scp>
            3X and specific initiation factors modulate
            <i>
              <scp>FMR</scp>
              1
            </i>
            repeat‐associated non‐AUG‐initiated translation

Linsalata, Alexander E.; He, Fang; Malik, Aatika; Glineburg, M. Rebecca; Green, Katelyn M.; Natla, Sam; Flores, Brittany; Krans, Amy; Archbold, Hilary C.; Fedak, Stephen J.; Barmada, Sami J.; Todd, Peter K.

doi:10.15252/embr.201847498

Cited by 61 publications

(54 citation statements)

References 121 publications

(281 reference statements)

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“…We used automated longitudinal microscopy to track survival of hundreds of individual neurons over days. Cortical Rat neurons expressing +1(CGG) 100 RAN-GFP demonstrated significant toxicity compared to GFP alone ( Fig 3I ) 43 . Treatment of +1(CGG) 100 RAN-GFP neurons with +1RAN ASO-1 significantly improved survival compared to Control ASO treatment, but had no effect on neurons expressing GFP alone.…”

Section: Resultsmentioning

confidence: 98%

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A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis

et al. 2020

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Repeat-associated non-AUG translation of expanded CGG repeats (CGG RAN) from the FMR1 5’ UTR produces toxic proteins that contribute to neurodegeneration in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Here we describe how unexpanded CGG repeats and their translation play conserved roles in regulating FMRP synthesis. In neurons, CGG RAN acts as an inhibitory upstream open reading frame to suppress basal FMRP production. Activation of mGluR5 receptors enhances FMRP synthesis. This enhancement requires both the CGG repeat and CGG RAN initiation sites. Using non-cleaving antisense oligonucleotides (ASOs), we selectively blocked RAN translation. This ASO blockade enhanced endogenous human neuronal FMRP expression. In human and rodent neurons, RAN blocking ASOs suppressed repeat toxicity and prolonged survival. These findings delineate a native function for CGG repeats and RAN translation in regulating basal and activity-dependent FMRP synthesis and demonstrate the therapeutic potential of modulating CGG RAN translation in fragile X-associated disorders.

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Section: Resultsmentioning

confidence: 98%

“…+1RAN ASO-1 treatment significantly decreased neuronal +1(CGG) 100 RAN-Venus expression ( Fig 3H ). Ectopic expression of CGG repeats is toxic in neurons 43 . We used automated longitudinal microscopy to track survival of hundreds of individual neurons over days.…”

Section: Resultsmentioning

confidence: 99%

A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis

et al. 2020

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“…DDX3X can also enhance IRES activity [74] and destabilize G-quadruplexes [75,76]. Intriguingly, recent studies propose a role of DDX3X in promoting [77] or repressing [78] repeat-associated, non-AUG (RAN) translation. Altogether, DDX3X proteins impact translation initiation, usually positively, resolving a variety of 5 0 UTR secondary structures, and control start codon fidelity.…”

Section: De Novo Variants In Ddx3x Are the Most Frequent Cause Of Unementioning

confidence: 99%

Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

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Piton

Lessel

et al. 2020

Biochemical Society Transactions

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Intellectual disability (ID) affects at least 1% of the population, and typically presents in the first few years of life. ID is characterized by impairments in cognition and adaptive behavior and is often accompanied by further delays in language and motor skills, as seen in many neurodevelopmental disorders (NDD). Recent widespread high-throughput approaches that utilize whole-exome sequencing or whole-genome sequencing have allowed for a considerable increase in the identification of these pathogenic variants in monogenic forms of ID. Notwithstanding this progress, the molecular and cellular consequences of the identified mutations remain mostly unknown. This is particularly important as the associated protein dysfunctions are the prerequisite to the identification of targets for novel drugs of these rare disorders. Recent Next-Generation sequencing-based studies have further established that mutations in genes encoding proteins involved in RNA metabolism are a major cause of NDD. Here, we review recent studies linking germline mutations in genes encoding factors mediating mRNA decay and regulators of translation, namely DCPS, EDC3, DDX6 helicase and ID. These RNA-binding proteins have well-established roles in mRNA decapping and/or translational repression, and the mutations abrogate their ability to remove 5′ caps from mRNA, diminish their interactions with cofactors and stabilize sub-sets of transcripts. Additional genes encoding RNA helicases with roles in translation including DDX3X and DHX30 have also been linked to NDD. Given the speed in the acquisition, analysis and sharing of sequencing data, and the importance of post-transcriptional regulation for brain development, we anticipate mutations in more such factors being identified and functionally characterized.

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“…Current analysis has also allowed the first direct detection, through peptide sequencing, of endogenous FMRpolyG peptide, the product of repeat-associated non-ATG (RAN) translation of the FMR1 mRNA. The abundance of the inclusion-associated ubiquitin-and SUMO-based modifiers supports a model for inclusion formation as the result of increased protein loads and elevated oxidative stress leading to maladaptive autophagy [46].…”

Section: Fragile X Tremor Ataxia Syndrome (Fxtas)mentioning

confidence: 71%

Non Coding CGG Repeat Expansion Diseases: An Update

2019

ARC Journal of Neuroscience

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In recent years neurological disorders specifically neurodegenerative diseases have been recognised worldwide and has been diagnosed more and more by clinicians with the ever improving genetic techniques and is currently considered a leading cause of disability and death right from young to elderly age and might surpass the diagnosis of cancer in future as predicted by World Health Organization(WHO).This type of disorders are common in both high-and low-income countries and it is only predicted to increase as time goes by. Expanded trinucleotide repeats are GGGGGC, CAG, CGG, CCG, CTG, CUG, GAA, and GCN etc in the genome are considered to cause major neurodegenerative diseases in general population. Pathogenesis is different for different repeats however time of onset of the disease and severity will depend on trinucleotide repeat number. So, these type of disease comes under category of Trinucleotide repeat expansion disorders (TREDs). Here in this article we further update about the disease spectrum caused by CGG repeat expansion. Founder haplotypes and haploinsufficiency have been identified recently and its analysis in families may reveal a shared haplotype. Attention should be paid not only to familial cases but also to sporadic cases presenting with similar clinical features otherwise the diagnosis can be missed in early stages.

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DDX 3X and specific initiation factors modulate FMR 1 repeat‐associated non‐AUG‐initiated translation

Cited by 61 publications

References 121 publications

A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis

A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis

Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

Non Coding CGG Repeat Expansion Diseases: An Update

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