Journal Article

Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features

Shaw, Pamela J., Ramesh, Tennore M., James, Evlyn, Hautbergue, Guillaume M., Higginbottom, Adrian, Shaw, Matthew P., Castelli, Lydia M., McGown, Alexander

2018

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - pathology / Animals / Animals, Genetically Modified / Biomedical and Life Sciences / Biomedicine / C9orf72 / C9orf72 Protein - genetics / C9orf72 Protein - metabolism / Cell Line / Cells, Cultured / Disease Models, Animal / Drug-screening / 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 / Neurology / Neurosciences / Pathology / SOD1 / Superoxide Dismutase-1 - metabolism / TDP-43 / Transfection / Zebrafish