RAN translation of C9ORF72-related dipeptide repeat proteins recapitulates hallmarks of motor neurone disease and identifies hypothermia as a therapeutic strategy in zebrafish

Abstract

ABSTRACTObjectiveHexanucleotide 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 DPRs as one of the main drivers of neuronal injury in cell and animal models.MethodsA pure RAN translation zebrafish model of C9orf72-ALS 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 zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS.ResultsHere we describe a pure RAN translation zebrafish model of C9orf72-ALS 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 cell models as well as embryonic C9orf72-ALS zebrafish.Interpretation:The transgenic model detailed in this paper provides a medium throughputin vivoresearch tool to further investigate the role of RAN-translation in C9orf72-ALS and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS.