PUBLICATION

RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy

Authors
Burrows, D.J., McGown, A., Abduljabbar, O., Castelli, L.M., Shaw, P.J., Hautbergue, G.M., Ramesh, T.M.
ID
ZDB-PUB-240902-1
Date
2024
Source
Annals of neurology   96(6): 1058-1069 (Journal)
Registered Authors
McGown, Alexander, Ramesh, Tennore
Keywords
none
MeSH Terms
  • Protein Biosynthesis/genetics
  • Protein Biosynthesis/physiology
  • Zebrafish*
  • C9orf72 Protein*/genetics
  • Animals, Genetically Modified*
  • Humans
  • Amyotrophic Lateral Sclerosis*/genetics
  • Amyotrophic Lateral Sclerosis*/metabolism
  • Amyotrophic Lateral Sclerosis*/therapy
  • Hypothermia, Induced/methods
  • Dipeptides*
  • Animals
  • Disease Models, Animal*
  • Frontotemporal Dementia/genetics
  • Frontotemporal Dementia/metabolism
(all 15)
PubMed
39215697 Full text @ Ann. Neurol.
Abstract
Objective Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models.
Methods A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.
Results Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.
Interpretation The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024.
Genes / Markers
Figures
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
sh697TgTransgenic Insertion
    sh698TgTransgenic Insertion
      sh699TgTransgenic Insertion
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
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        Fish
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        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        DsRedEFGDsRed
        1 - 1 of 1
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        Mapping
        No data available
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        Citation
        Burrows, D.J., McGown, A., Abduljabbar, O., Castelli, L.M., Shaw, P.J., Hautbergue, G.M., Ramesh, T.M. (2024) RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy. Annals of neurology. 96(6):1058-1069.