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

Swinnen, Bart; Bento‐Abreu, André; Gendron, Tania F.; Boeynaems, Steven; Bogaert, Elke; Nuyts, Rik; Timmers, Mieke; Scheveneels, Wendy; Hersmus, Nicole; Wang, Jiou; Mizielinska, Sarah; Isaacs, Adrian M.; Petrucelli, Leonard; Lemmens, Robin; Damme, Philip Van; Bosch, Ludo Van Den; Robberecht, Wim

doi:10.1007/s00401-017-1796-5

Cited by 114 publications

(126 citation statements)

References 55 publications

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“…The model presented here, importantly, display TDP-43 pathology and replicates haploinsu ciency as a major contributor to C9orf72 ALS rather than a full ablation of C9or72 loss-offunction model. Intriguingly, the motor phenotypes observed in C9-miR zebra sh are consistent with several other zebra sh ALS models, including zebra sh model expressing C9orf72-related repeat expansions or DPR 28,42,43 . However, the presence a reduced level of C9orf72 mRNA or protein in these models, as in ALS/FTD, was not examined in these studies.…”

Section: Discussionsupporting

confidence: 84%

Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

Butti¹,

Giacomotto

Patten³

2020

Preprint

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A hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). Reduced levels of C9orf72 mRNA and protein have been found in ALS/FTD patients, but the role of this protein in disease pathogenesis is still poorly understood. Here, we report the generation and characterization of a stable C9orf72 loss-of-function (LOF) model in the zebrafish. We show that reduced C9orf72 function leads to motor defects, muscle atrophy, motor neuron loss and mortality in early larval and adult stages. Analysis of the structure and function of the neuromuscular junctions (NMJs) of the larvae, reveal a significant reduction in the number of presynaptic and postsynaptic structures and an impaired release of quantal synaptic vesicles at the NMJ. Strikingly, we demonstrate a downregulation of SV2a upon C9orf72-LOF and a reduced rate of synaptic vesicle cycling. Furthermore, we show a reduced number and size of Rab3a-postive synaptic puncta at NMJs. Altogether, these results reveal a key function for C9orf72 in the control of presynaptic vesicle trafficking and release at the zebrafish larval NMJ. Our study demonstrates a novel role for C9orf72 in ALS/FTD pathogenesis, where it regulates synaptic vesicle release and neuromuscular functions.

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Section: Discussionsupporting

confidence: 84%

Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

Butti¹,

Giacomotto

Patten³

2020

Preprint

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“…To investigate DPR-only toxicity, models have been generated where individual DPRs are expressed. When overexpressed, polypeptides of the arginine-rich DPRs glycine-arginine (GR) and proline-arginine (PR) have the greatest potential to induce neurotoxicity in Drosophila, C. elegans and zebrafish [66,67,80,81,[83][84][85][86][87][88], but polypeptides of glycine-alanine (GA) also cause toxicity in Drosophila, zebrafish, chick embryo and mouse models [67,80,[89][90][91][92][93].The expression of 50 or 69 GA repeats via adenovirus-mediated delivery into neonatal mouse brain or zygote injection for (mostly) neuronal expression of 149 GA repeats induce development of primarily motor phenotypes [92][93][94]. However, memory deficits and increased anxiety were also identified in the (GA) 50 model [93].…”

Section: C9orf72mentioning

confidence: 99%

Review: Modelling the pathology and behaviour of frontotemporal dementia

Solomon

Mitchell

Salcher-Konrad

et al. 2019

Neuropathology Appl Neurobio

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Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.

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“…In order to address this hypothesis, we used zebrafish (Danio rerio), a vertebrate model used to easily study normal and pathological events in the nervous system [40]- [42]. A number of genetic models in zebrafish have been established for a range of neurodegenerative disorders, including ALS [43]- [49].…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of Neurofilament Light b splicing andmisbalance in zebrafish

Demy

Campanari

Munoz-Ruiz

et al. 2020

Preprint

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Neurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in their differentiation, establishment and maintenance of their morphology and mechanical strength. The de novo assembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit, NEFL, which expression is reduced in motor neurons in Amyotrophic Lateral Sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologue neflb, which encodes two different isoforms via splicing of the primary transcript (neflbE4 and neflbE3). In vivo imaging showed that neflb is crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects NF assembly and motor axon growth, with resulting motor deficits. This equilibrium is also disrupted upon partial depletion of TDP-43, a RNA binding protein that is mislocalized into cytoplasmic inclusions in ALS. The study supports interaction of NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.

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

Cited by 114 publications

References 55 publications

Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

Review: Modelling the pathology and behaviour of frontotemporal dementia

Functional characterization of Neurofilament Light b splicing andmisbalance in zebrafish

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