The hexanucleotide G4C2 repeat expansion in the first intron of the C9ORF72 gene accounts for the majority of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) cases. Numerous studies have indicated the toxicity of dipeptide repeats (DPRs), which are produced via repeat-associated non-AUG (RAN) translation from the repeat expansion, and accumulate in the brain of C9FTD/ALS patients. Mouse models expressing the human C9ORF72 repeat and/ or DPRs show variable pathological, functional and behavioral characteristics of FTD and ALS. Here, we report a new Tet-on inducible mouse model that expresses 36× pure G4C2 repeats with 100-bp upstream and downstream human flanking regions. Brain-specific expression causes the formation of sporadic sense DPRs aggregates upon 6 months of dox induction, but no apparent neurodegeneration. Expression in the rest of the body evokes abundant sense DPRs in multiple organs, leading to weight loss, neuromuscular junction disruption, myopathy and a locomotor phenotype within the time frame of 4 weeks. We did not observe any RNA foci or pTDP-43 pathology. Accumulation of DPRs and the myopathy phenotype could be prevented when 36× G4C2 repeat expression was stopped after 1 week. After 2 weeks of expression, the phenotype could not be reversed, even though DPR levels were reduced. In conclusion, expression of 36× pure G4C2 repeats including 100-bp human flanking regions is sufficient for RAN translation of sense DPRs, and evokes a functional locomotor phenotype. Our inducible mouse model suggests that early diagnosis and treatment are important for C9FTD/ALS patients.

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Disease Models & Mechanisms
Department of Clinical Genetics

Riemslagh, F., van der Toorn, E.C. (Esmay C.), Verhagen, R. F. M., Maas, A., Bosman, L., Hukema, R., & Willemsen, R. (2021). Inducible expression of human C9ORF72 36× G4C2 hexanucleotide repeats is sufficient to cause RAN translation and rapid muscular atrophy in mice. Disease Models & Mechanisms, 14(2). doi:10.1242/dmm.044842