RETRACTED ARTICLE: A new inducible transgenic mouse model for C9orf72-associated GGGGCC repeat expansion supports a gain-of-function mechanism in C9orf72-associated ALS and FTD

Hukema, Renate K.; Riemslagh, Fréderike W.; Melhem, Shamiram; Linde, Herma C. van der; Severijnen, Lies‐Anne; Edbauer, Dieter; Maas, Alex; Charlet‐Berguerand, Nicolas; Willemsen, Rob; Swieten, John van

doi:10.1186/s40478-014-0166-y

Cited by 24 publications

(11 citation statements)

References 12 publications

(11 reference statements)

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“…In support of a gain‐of‐function mechanism, recent work shows that AAV‐mediated expression of 66 GGGGCC repeats in the adult mouse brain induces key features of ALS/FTD, such as TDP‐43 pathology and behavioral deficits 6. A different study, using transgenic mice with inducible expression of hexanucleotide (GGGGCC) repeats, found ubiquitinated inclusions, but these inclusions were not detected in neuronal populations relevant for ALS/FTD and no motor phenotype was found 25. Our finding that loss of C9orf72 function does not lead to motor neuron disease in mice has consequences for therapeutic strategies, because it indicates that ASOs directed at the repeat expansion that also lower C9ORF72 expression are unlikely to have negative side effects due to reduced C9ORF72 expression.…”

Section: Discussionmentioning

confidence: 99%

C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits

Koppers

Blokhuis

Westeneng

et al. 2015

Annals of Neurology

232

189

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ObjectiveHow hexanucleotide (GGGGCC) repeat expansions in C9ORF72 cause amyotrophic lateral sclerosis (ALS) remains poorly understood. Both gain‐ and loss‐of‐function mechanisms have been proposed. Evidence supporting these mechanisms in vivo is, however, incomplete. Here we determined the effect of C9orf72 loss‐of‐function in mice.MethodsWe generated and analyzed a conditional C9orf72 knockout mouse model. C9orf72fl/fl mice were crossed with Nestin‐Cre mice to selectively remove C9orf72 from neurons and glial cells. Immunohistochemistry was performed to study motor neurons and neuromuscular integrity, as well as several pathological hallmarks of ALS, such as gliosis and TDP‐43 mislocalization. In addition, motor function and survival were assessed.ResultsNeural‐specific ablation of C9orf72 in conditional C9orf72 knockout mice resulted in significantly reduced body weight but did not induce motor neuron degeneration, defects in motor function, or altered survival.InterpretationOur data suggest that C9orf72 loss‐of‐function, by itself, is insufficient to cause motor neuron disease. These results may have important implications for the development of therapeutic strategies for C9orf72‐associated ALS. Ann Neurol 2015;78:426–438

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Section: Discussionmentioning

confidence: 99%

C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits

Koppers

Blokhuis

Westeneng

et al. 2015

Annals of Neurology

232

189

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show abstract

“…The GGGGCC repeat RNA forms foci in cells, animal models and patients and has been shown to be able to induce neuronal cell death and to sequester RNA binding proteins [8, 15, 20, 32]. However, there is only a weak correlation between RNA foci and neurodegeneration in patients [33–35]. In zebrafish RNA injection of 8x, 38x, and 72x GGGGCC repeats has been shown to cause RNA foci and cell death by apoptosis in a repeat length dependent manner [9].…”

Section: Discussionmentioning

confidence: 99%

Glycine-alanine dipeptide repeat protein contributes to toxicity in a zebrafish model of C9orf72 associated neurodegeneration

Ohki

Wenninger-Weinzierl

Hruscha

et al. 2017

Mol Neurodegeneration

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BackgroundThe most frequent genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the expansion of a GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 (C9orf72) locus. The pathological hallmarks observed in C9orf72 repeat expansion carriers are the formation of RNA foci and deposition of dipeptide repeat (DPR) proteins derived from repeat associated non-ATG (RAN) translation. Currently, it is unclear whether formation of RNA foci, DPR translation products, or partial loss of C9orf72 predominantly drive neurotoxicity in vivo. By using a transgenic approach in zebrafish we address if the most frequently found DPR in human ALS/FTLD brain, the poly-Gly-Ala (poly-GA) protein, is toxic in vivo.MethodWe generated several transgenic UAS responder lines that express either 80 repeats of GGGGCC alone, or together with a translation initiation ATG codon forcing the translation of GA80-GFP protein upon crossing to a Gal4 driver. The GGGGCC repeat and GA80 were fused to green fluorescent protein (GFP) lacking a start codon to monitor protein translation by GFP fluorescence.ResultsZebrafish transgenic for the GGGGCC repeat lacking an ATG codon showed very mild toxicity in the absence of poly-GA. However, strong toxicity was induced upon ATG initiated expression of poly-GA, which was rescued by injection of an antisense morpholino interfering with start codon dependent poly-GA translation. This morpholino only interferes with GA80-GFP translation without affecting repeat transcription, indicating that the toxicity is derived from GA80-GFP.ConclusionThese novel transgenic C9orf72 associated repeat zebrafish models demonstrate poly-GA toxicity in zebrafish. Reduction of poly-GA protein rescues toxicity validating this therapeutic approach to treat C9orf72 repeat expansion carriers. These novel animal models provide a valuable tool for drug discovery to reduce DPR associated toxicity in ALS/FTLD patients with C9orf72 repeat expansions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0146-8) contains supplementary material, which is available to authorized users.

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“…The authors are retracting this article [1]. Careful re-examination of the transgenic mice used in this study has indicated that they contain a transgenic sequence containing a 90CGG repeat, associated with fragile X-associated tremor/ataxia syndrome (FXTAS).…”

Section: Retraction Notementioning

confidence: 99%

Retraction Note to: A new inducible transgenic mouse model for C9orf72-associated GGGGCC repeat expansion supports a gain-of-function mechanism in C9orf72-associated ALS and FTD

Hukema

Riemslagh

Melhem

et al. 2016

acta neuropathol commun

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RETRACTED ARTICLE: A new inducible transgenic mouse model for C9orf72-associated GGGGCC repeat expansion supports a gain-of-function mechanism in C9orf72-associated ALS and FTD

Cited by 24 publications

References 12 publications

C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits

C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits

Glycine-alanine dipeptide repeat protein contributes to toxicity in a zebrafish model of C9orf72 associated neurodegeneration

Retraction Note to: A new inducible transgenic mouse model for C9orf72-associated GGGGCC repeat expansion supports a gain-of-function mechanism in C9orf72-associated ALS and FTD

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