Glucose hypometabolism prompts RAN translation and exacerbates C9orf72-related ALS/FTD phenotypes

The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, but its role in disease pathogenesis is unknown. Here, we show alterations in glucose metabolic pathways and ATP levels in the brains of asymptomatic C9-BAC mice. We find that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also show that one of the arginine-rich DPRs (PR) could directly contribute to glucose metabolism and metabolic stress by inhibiting glucose uptake in neurons. Our findings provide a potential mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and suggest a feedforward loop model with potential opportunities for therapeutic intervention. Prolonged imbalance in glucose metabolism increases RAN translation and accumulation of DPRs, heightening neuronal vulnerability in in vitro and in vivo models of C9orf72-ALS/FTD.C9-BAC mice show dysregulated brain metabolite production. Glucose homeostasis is critical to maintaining RAN translation of the C9 repeats at low levels. Neurons bearing the ALS/FTD causative C9orf72 mutation are more vulnerable to glucose deficiencies than wild-type neurons. Prolonged imbalance in glucose metabolism increases RAN translation and accumulation of DPRs, heightening neuronal vulnerability in in vitro and in vivo models of C9orf72-ALS/FTD.