PUBLICATION
Reduction of oxidative stress suppresses poly-GR mediated toxicity in zebrafish embryos
- Authors
- Riemslagh, F.W., Verhagen, R.F.M., van der Toorn, E.C., Smits, D.J., Quint, W.H., van der Linde, H.C., van Ham, T.J., Willemsen, R.
- ID
- ZDB-PUB-211026-15
- Date
- 2021
- Source
- Disease models & mechanisms 14(11): (Journal)
- Registered Authors
- van der Linde, Herma, van Ham, Tjakko
- Keywords
- ALS, C9ORF72, FTD, Neurodegeneration, Oxidative stress, Poly-GR
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis*/pathology
- Animals
- C9orf72 Protein/genetics
- Frontotemporal Dementia*/genetics
- Frontotemporal Dementia*/metabolism
- Oxidative Stress
- Zebrafish/metabolism
- PubMed
- 34693978 Full text @ Dis. Model. Mech.
Citation
Riemslagh, F.W., Verhagen, R.F.M., van der Toorn, E.C., Smits, D.J., Quint, W.H., van der Linde, H.C., van Ham, T.J., Willemsen, R. (2021) Reduction of oxidative stress suppresses poly-GR mediated toxicity in zebrafish embryos. Disease models & mechanisms. 14(11):.
Abstract
The hexanucleotide repeat expansion (G4C2) 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 post fertilization (dpf) embryos. Poly-GR can be specifically detected in protein homogenates from injected zebrafish and in frontal cortexes of C9FTD/ALS cases. Poly-GR expression further elevated MitoSOX levels in zebrafish embryos, indicative of 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping