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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by motor neuron loss, leading to progressive muscle weakness and eventual death, primarily due to respiratory failure
At the single cell stage zebrafish embryos were injected with a DNA construct containing 89 chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeats (Fig. 1a, Additional file 1)
Using this C9orf72 zebrafish model we have identified novel insights into the pathogenesis of C9-amyotrophic lateral sclerosis/fronto-temporal dementia (ALS/frontotemporal dementia (FTD))
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by motor neuron loss, leading to progressive muscle weakness and eventual death, primarily due to respiratory failure. The remaining 90% of ALS cases are caused by complex genetic and environmental interactions which are currently not well understood, this is known as sporadic-ALS (sALS). Mutations in multiple genetic loci have been identified as causes of ALS including the SOD1 and TARDBP loci. See Amyotrophic Lateral Sclerosis Online Genetics Database for comprehensive information (http://alsod.iop.kcl.ac.uk/). The most common known genetic cause of ALS and frontotemporal dementia (FTD) is a hexanucleotide expansion within the first intron of the C9orf gene [11, 32]. Carriers of the C9orf hexanucleotide expansion may show symptoms of ALS or FTD exclusively, but can present with symptoms of both diseases concurrently
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
