Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis

Ciura, Sorana; Lattante, Serena; Ber, Isabelle Le; Latouche, Morwena; Tostivint, Hervé; Brice, Alexis; Kabashi, Edor

doi:10.1002/ana.23946

Cited by 297 publications

(292 citation statements)

References 31 publications

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“…The contribution of this reduction to neuronal death is not established, although loss of C9orf72 during embryonic development is associated with motor deficits in zebrafish (23).…”

Section: Significancementioning

confidence: 99%

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

Lagier‐Tourenne

Baughn

Rigo

et al. 2013

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

521

573

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Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.E xpanded hexanucleotide repeats in the first intron of the chromosome 9 open reading frame 72 (C9orf72) gene were recently identified (1, 2) as the most common genetic cause of ALS, frontotemporal degeneration (FTD), or concomitant ALS/ FTD (3, 4). The mechanisms by which the expanded repeats cause neurodegeneration are unknown, but leading candidate mechanisms are RNA-mediated toxicity, loss of the C9orf72 gene function (from reduced C9orf72 produced by the allele with the expansion), or a combination of the two.RNA-mediated toxicity from nucleotide repeat expansion was initially described for CUG expansion in the RNA encoded by the DMPK gene in myotonic muscular dystrophy (5). A consensus view is that RNA toxicity plays a crucial role in a variety of repeat expansion disorders (6). A hallmark of these disorders is the accumulation of expanded transcripts into nuclear RNA foci (7). RNAs harboring a long stretch of repeats are thought to fold into stable structures and sequester RNA binding proteins, which, in turn, sets off a molecular cascade leading to neurodegeneration (7). In myotonic dystrophy, sequestration and functional disruption of the muscleblind-like family of RNA binding proteins are associated with specific splicing and expression changes in affected tissues (5,(8)(9)(10)(11)(12).Sequestration of one or more RNA binding proteins into pathological RNA foci has ...

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“…The contribution of this reduction to neuronal death is not established, although loss of C9orf72 during embryonic development is associated with motor deficits in zebrafish (23).…”

Section: Significancementioning

confidence: 99%

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

Lagier‐Tourenne

Baughn

Rigo

et al. 2013

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

521

573

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“…Because of reduced expression of C9orf72 transcripts in brain tissue and cells [3,50], a lossof-function mechanism has been proposed. Knockdown of C9orf72 in zebrafish and C. elegans indeed resulted in a neuronal phenotype [8,44]. However, several mouse models with a general or neuron-specific deletion of C9orf72 did not develop clinical or pathological signs of motor neuron disease [2,27,28,35,42].…”

Section: Electronic Supplementary Materialsmentioning

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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“…In healthy individuals, the number of repeats ranges from 2 to 23. In patients with ALS and FTLD, sixty to several hundred G4C2 repeats are found in the C9ORF72 gene 4,5 .…”

Section: C9orf72 Interaction With Cofilin Modulates Actin Dynamics Inmentioning

confidence: 99%

C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

et al. 2016

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Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis

Cited by 297 publications

References 31 publications

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

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

C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

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