PUBLICATION
Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features
- Authors
- Shaw, M.P., Higginbottom, A., McGown, A., Castelli, L.M., James, E., Hautbergue, G.M., Shaw, P.J., Ramesh, T.M.
- ID
- ZDB-PUB-181127-14
- Date
- 2018
- Source
- Acta neuropathologica communications 6: 125 (Journal)
- Registered Authors
- McGown, Alexander, Tennore, Ramesh
- Keywords
- Amyotrophic lateral sclerosis, C9orf72, Drug-screening, SOD1, TDP-43, Zebrafish
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis/genetics*
- Amyotrophic Lateral Sclerosis/pathology*
- Animals
- Animals, Genetically Modified
- C9orf72 Protein/genetics*
- C9orf72 Protein/metabolism
- Cell Line
- Cells, Cultured
- Disease Models, Animal
- Embryo, Nonmammalian
- Frontotemporal Dementia/genetics*
- Frontotemporal Dementia/pathology*
- Gene Expression Regulation/genetics
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Heat-Shock Response
- Humans
- Locomotion/genetics
- Mice
- Motor Neurons/pathology
- Muscles/metabolism
- Muscles/pathology
- Muscles/ultrastructure
- Superoxide Dismutase-1/metabolism
- Transfection
- Zebrafish
- PubMed
- 30454072 Full text @ Acta Neuropathol Commun
Citation
Shaw, M.P., Higginbottom, A., McGown, A., Castelli, L.M., James, E., Hautbergue, G.M., Shaw, P.J., Ramesh, T.M. (2018) Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features. Acta neuropathologica communications. 6:125.
Abstract
A hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is the most prevalent cause of amyotrophic lateral sclerosis/fronto-temporal dementia (ALS/FTD). Current evidence suggests HREs induce neurodegeneration through accumulation of RNA foci and/or dipeptide repeat proteins (DPR). C9orf72 patients are known to have transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy, but whether there is further cross over between C9orf72 pathology and the pathology of other ALS sub-types has yet to be revealed.To address this, we generated and characterised two zebrafish lines expressing C9orf72 HREs. We also characterised pathology in human C9orf72-ALS cases. In addition, we utilised a reporter construct that expresses DsRed under the control of a heat shock promoter, to screen for potential therapeutic compounds.Both zebrafish lines showed accumulation of RNA foci and DPR. Our C9-ALS/FTD zebrafish model is the first to recapitulate the motor deficits, cognitive impairment, muscle atrophy, motor neuron loss and mortality in early adulthood observed in human C9orf72-ALS/FTD. Furthermore, we identified that in zebrafish, human cell lines and human post-mortem tissue, C9orf72 expansions activate the heat shock response (HSR). Additionally, HSR activation correlated with disease progression in our C9-ALS/FTD zebrafish model. Lastly, we identified that the compound ivermectin, as well as riluzole, reduced HSR activation in both C9-ALS/FTD and SOD1 zebrafish models.Thus, our C9-ALS/FTD zebrafish model is a stable transgenic model which recapitulates key features of human C9orf72-ALS/FTD, and represents a powerful drug-discovery tool.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping