Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72

Zhu, Qiang; Jiang, Jie; Gendron, Tania F.; McAlonis-Downes, Melissa; Jiang, LuLin; Taylor, Amy E; Garcia, Sandra Diaz; Dastidar, Somasish Ghosh; Rodrí­guez, Marí­a José; King, Patrick J.; Zhang, Yongjie; Spada, Albert R. La; Xu, Huaxi; Petrucelli, Leonard; Ravits, John; Cruz, Sandrine Da; Lagier‐Tourenne, Clotilde; Cleveland, Don W.

doi:10.1038/s41593-020-0619-5

Cited by 169 publications

(180 citation statements)

References 56 publications

Supporting

Mentioning

170

Contrasting

Order By: Relevance

“…We found that expression of GGGGCC repeat expansions in our C9-miR exacerbated toxicity and resulted in death of zebra sh by 6 dpf ( Figure S1). Such a synergistic interplay between reduced C9orf72 function and repeat-dependent gain of toxicity was observed in a recent study by Zhu and colleagues 46 .…”

Section: Discussionmentioning

confidence: 54%

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

Butti¹,

Giacomotto

Patten³

2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 54%

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

Butti¹,

Giacomotto

Patten³

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In summary, our results indicate that the G4C2 expansion in C9orf72 interferes with multiple nuclear functions, culminating in an inhibition of protein biogenesis, an outcome that would be especially harmful to neuronal cells. These dominant toxic effects might be further aggravated by a loss of function of the endogenous C9ORF72 protein, which is thought to play a role in cellular quality control (Boivin et al, 2020;Sellier et al, 2016;Sullivan et al, 2016;Yang et al, 2016;Zhu et al, 2020). Further research on the relative contribution of the different toxic mechanisms will be important in developing therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its location in a noncoding part of the gene, the G4C2 expansion can alter the expression level of the C9ORF72 protein (Rizzu et al, 2016;Waite et al, 2014). However, C9orf72 knockout mouse models have failed to fully recapitulate ALS-or FTD-related neurodegenerative phenotypes, suggesting that loss of C9ORF72 protein is not the only contributor to pathology (Burberry et al, 2016;Burberry et al, 2020;Koppers et al, 2015;O'Rourke et al, 2016;Sudria-Lopez et al, 2016;Zhu et al, 2020). Toxic functions induced by this expansion have been studied in various cellular and animal models, and non-exclusive RNA-and protein-based mechanisms of toxicity have been proposed.…”

Section: Both Loss-and Gain-of-function Mechanisms Have Been Suggestementioning

confidence: 99%

Multiple pathways of toxicity induced byC9orf72dipeptide repeat aggregates and G₄C₂RNA in a cellular model

Frottin

Pérez‐Berlanga

et al. 2020

Preprint

View full text Add to dashboard Cite

The most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia is a G4C2 repeat expansion in the C9orf72 gene. This expansion gives rise to translation of aggregating dipeptide repeat (DPR) proteins, including poly-GA as the most abundant species. However, gain of toxic function effects have been attributed to either the DPRs or the pathological G4C2 RNA. Here we analyzed in a cellular model the relative toxicity of DPRs and RNA. Cytoplasmic poly-GA aggregates, generated in the absence of G4C2 RNA, interfered with nucleocytoplasmic protein transport, but had little effect on cell viability. In contrast, nuclear poly-GA was more toxic, impairing nucleolar protein quality control and protein biosynthesis. Production of the G4C2 RNA strongly reduced viability independent of DPR translation and caused pronounced inhibition of nuclear mRNA export and protein biogenesis. Thus, while the toxic effects of G4C2 RNA predominate, DPRs exert additive effects that may contribute to pathology.

show abstract

“…The relative contribution of these 3 mechanisms remains to be established as well as the molecular pathways leading to motor neuron degeneration. It is however becoming clearer that haploinsufficiency might contribute to the disease process in synergy with the gain-of-toxicity mechanism [ 56 ]. Animal models can then provide answers on the different mechanisms involved and consequently help to develop a specific treatment for patients with C9orf72 ALS.…”

Section: The C9orf72 Gene Associated With Alsmentioning

confidence: 99%

Modelling C9orf72-Related Amyotrophic Lateral Sclerosis in Zebrafish

2020

View full text Add to dashboard Cite

A hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and its discovery has revolutionized our understanding of this devastating disease. Model systems are a valuable tool for studying ALS pathobiology and potential therapies. The zebrafish (Danio rerio) has particularly become a useful model organism to study neurological diseases, including ALS, due to high genetic and physiological homology to mammals, and sensitivity to various genetic and pharmacological manipulations. In this review we summarize the zebrafish models that have been used to study the pathology of C9orf72-related ALS. We discuss their value in providing mechanistic insights and their potential use for drug discovery.

show abstract

Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72

Cited by 169 publications

References 56 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

Multiple pathways of toxicity induced byC9orf72dipeptide repeat aggregates and G₄C₂RNA in a cellular model

Modelling C9orf72-Related Amyotrophic Lateral Sclerosis in Zebrafish

Contact Info

Product

Resources

About

Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72

Cited by 169 publications

References 56 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

Multiple pathways of toxicity induced byC9orf72dipeptide repeat aggregates and G4C2RNA in a cellular model

Modelling C9orf72-Related Amyotrophic Lateral Sclerosis in Zebrafish

Contact Info

Product

Resources

About

Multiple pathways of toxicity induced byC9orf72dipeptide repeat aggregates and G₄C₂RNA in a cellular model