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

Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model

The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases