Andrew T Nelson, Maria Elena Cicardi, Shashirekha S Markandaiah, John Ys Han, Nancy J Philp, Emily Welebob, Aaron R Haeusler, Piera Pasinelli, Giovanni Manfredi, Hibiki Kawamata, Davide Trotti
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...
April 29, 2024: EMBO Reports