Reduction of oxidative stress suppresses poly-GR-mediated toxicity in zebrafish embryos

The hexanucleotide (G4C2)-repeat expansion in the C9ORF72 gene is the most common pathogenic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This repeat expansion can be translated into dipeptide repeat proteins (DPRs), and distribution of the poly-GR DPR correlates w...

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Published inDisease models & mechanisms Vol. 14; no. 11
Main Authors Riemslagh, Fréderike W, Verhagen, Rob F M, van der Toorn, Esmay C, Smits, Daphne J, Quint, Wim H, van der Linde, Herma C, van Ham, Tjakko J, Willemsen, Rob
Format Journal Article
LanguageEnglish
Published England The Company of Biologists Ltd 01.11.2021
The Company of Biologists
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Summary:The hexanucleotide (G4C2)-repeat expansion in the C9ORF72 gene is the most common pathogenic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This repeat expansion can be translated into dipeptide repeat proteins (DPRs), and distribution of the poly-GR DPR correlates with neurodegeneration in postmortem C9FTD/ALS brains. Here, we assessed poly-GR toxicity in zebrafish embryos, using an annexin A5-based fluorescent transgenic line (secA5) that allows for detection and quantification of apoptosis in vivo. Microinjection of RNA encoding poly-GR into fertilized oocytes evoked apoptosis in the brain and abnormal motor neuron morphology in the trunk of 1-4-days postfertilization embryos. Poly-GR can be specifically detected in protein homogenates from injected zebrafish and in the frontal cortexes of C9FTD/ALS cases. Poly-GR expression further elevated MitoSOX levels in zebrafish embryos, indicating oxidative stress. Inhibition of reactive oxygen species using Trolox showed full suppression of poly-GR toxicity. Our study indicates that poly-GR can exert its toxicity via oxidative stress. This zebrafish model can be used to find suppressors of poly-GR toxicity and identify its molecular targets underlying neurodegeneration observed in C9FTD/ALS.
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Handling Editor: E. Elizabeth Patton
ISSN:1754-8403
1754-8411
DOI:10.1242/dmm.049092