Survival and Motor Phenotypes in FVB C9-500 ALS/FTD BAC Transgenic Mice Reproduced by Multiple Labs

Mordes et al. (2020) did not detect the survival or motor phenotypes in C9orf72 BAC transgenic mice originally described by Liu et al. (2016). We discuss methodological differences between the Mordes and Liu studies, several additional studies in which survival and motor phenotypes were found, and possible environmental and genetic effects. First, Nguyen et al. (2020) showed robust ALS/FTD phenotypes in C9-BAC versus non-transgenic (NT) mice and that α-GA1 treatment improved survival, behavior, and neurodegeneration. The groups of Gelbard and Saxena also show decreased survival of C9-BAC versus NT mice and neuropathological and behavioral deficits similar to those shown by Liu et al. (2016). Although FVB/N mice can have seizures, increases in seizure severity and death of C9 and NT animals, which may mask C9 disease phenotypes, have been observed in recent C9-500 FVB/NJ-bred cohorts. In summary, we provide an update on phenotypes seen in FVB C9-BAC mice and additional details to successfully use this model. This Matters Arising Response paper addresses the Mordes et al. (2020) Matters Arising paper, published concurrently in Neuron. •Behavioral and pathological phenotypes in C9orf72 BAC mice found in multiple labs•Environmental conditions can modulate phenotype severity in C9-BAC mice•Recent increased seizures in FVB-N/J C9 and NT mice may mask ALS/FTD phenotypes•C9-BAC mice on Janvier Labs FVB-N background show increased disease penetrance Liu et al. (2016) previously described a BAC transgenic model of C9orf72 ALS/FTD. The molecular and pathological features in this model are now detected by multiple independent groups. Methodological factors can affect detection of ALS/FTD phenotypes. Additionally, environment and FVB strain background are important phenotypic modifiers in this model.