C9orf72 nucleotide repeat structures initiate molecular cascades of disease

Haeusler, Aaron R.; Donnelly, Christopher J.; Periz, Goran; Simko, Eric A J; Shaw, Patrick G.; Kim, Min‐Sik; Maragakis, Nicholas J.; Troncoso, Juan C.; Pandey, Akhilesh; Sattler, Rita; Rothstein, Jeffrey D.; Wang, Jiou

doi:10.1038/nature13124

Cited by 821 publications

(1,124 citation statements)

References 47 publications

(65 reference statements)

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“…These structures are postulated to modulate gene expression at transcriptional and posttranscriptional levels, and to promote nucleolar stress in ways that contribute to age-dependent motor neuron dropout (17,32,(36)(37)(38). Together with our results, these studies suggest that various G4 structures may play important roles in ensuring motor neuron viability.…”

Section: Discussionsupporting

confidence: 68%

“…Recent findings have implicated G4 structures formed by GGGGCC hexanucleotide repeats found in the C9ORF72 gene in the pathogenesis of ALS and FTD (17,32,(36)(37)(38). These structures are postulated to modulate gene expression at transcriptional and posttranscriptional levels, and to promote nucleolar stress in ways that contribute to age-dependent motor neuron dropout (17,32,(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

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G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

Ivanov

O’Day

Emara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

282

270

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Angiogenin (ANG) is a stress-activated ribonuclease that promotes the survival of motor neurons. Ribonuclease inactivating point mutations are found in a subset of patients with ALS, a fatal neurodegenerative disease with no cure. We recently showed that ANG cleaves tRNA within anticodon loops to produce 5′-and 3′-fragments known as tRNA-derived, stress-induced RNAs (tiRNAs). Selected 5′-tiRNAs (e.g., tiRNA Ala , tiRNA Cys ) cooperate with the translational repressor Y-box binding protein 1 (YB-1) to displace the cap-binding complex eIF4F from capped mRNA, inhibit translation initiation, and induce the assembly of stress granules (SGs). Here, we show that translationally active tiRNAs assemble unique G-quadruplex (G4) structures that are required for translation inhibition. We show that tiRNA Ala binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5′-tiDNA Ala (the DNA equivalent of 5′-tiRNA Ala ) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5′-tiDNA Ala also assembles a G4 structure that allows it to enter motor neurons spontaneously and trigger a neuroprotective response in a YB-1-dependent manner. Remarkably, the ability of 5′-tiRNA Ala to induce SG assembly is inhibited by G4 structures formed by pathological GGGGCC repeats found in C9ORF72, the most common genetic cause of ALS, suggesting that functional interactions between G4 RNAs may contribute to neurodegenerative disease.tRNA | angiogenin | stress | C9ORF72 | amyotrophic lateral sclerosis

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

Ivanov

O’Day

Emara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

282

270

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“…The p35-S and p35-AS plasmids, containing ~ 35 GGG GCC or ~ 35 CCC CGG repeats, were generated by EcoRI digestion of the pATG75 construct [25] and ligation into the pCMV6-Entry vector. Plasmids pUAST91, containing 91 GGG GCC hexanucleotide repeats, and pUAST108RO [33], containing 108 GGG GCC stop codon-interrupted repeats, were digested with EcoRI/NotI and KpnI, respectively, and the repeat was subcloned into the pCMV6-Entry vector to generate the p90-S and the p108RO-S plasmids.…”

Section: Plasmids and In Vitro Rna Transcriptionmentioning

confidence: 99%

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGG GCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.

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“…Several of these proteins associate with TDP43 [77], hinting at conserved mechanisms of cellular dysfunction in myotonic dystrophy and motor neuron disease. Similarly, C9orf72 RNA transcripts harboring G 4 C 2 expansion mutations form unique G-quadruplex secondary structures and DNA-RNA hybrids that sequester RNA-binding proteins [119,120] (Fig. 1).…”

Section: Sequestrationmentioning

confidence: 99%

“…1). Many of the proteins bound by G 4 C 2 repeats are required for normal RNA processing, including nucleolin, ADAR, hnRNP A1, hnRNP H, SC35, and serine/ arginine-rich splicing factor 1 and serine/arginine-rich splicing factor 2 [66,68,119,121,122], suggesting that neuronal toxicity in ALS might arise from a functional depletion of these essential factors. If so, then blocking the repeat domain might prevent downstream toxicity.…”

Section: Sequestrationmentioning

confidence: 99%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

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The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

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C9orf72 nucleotide repeat structures initiate molecular cascades of disease

Cited by 821 publications

References 47 publications

G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

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