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.
Amyotrophic Lateral Sclerosis , C9orf72 Protein , Frontotemporal Dementia , Glucose , Phenotype , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , C9orf72 Protein/genetics , C9orf72 Protein/metabolism , Animals , Frontotemporal Dementia/genetics , Frontotemporal Dementia/metabolism , Frontotemporal Dementia/pathology , Glucose/metabolism , Mice , Humans , Protein Biosynthesis , Neurons/metabolism , Brain/metabolism , Brain/pathology , Disease Models, Animal , DNA Repeat Expansion/genetics , Mice, Transgenic , Adenosine Triphosphate/metabolism
