Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes

Trotti, D.; Nelson, A. T.; Cicardi, M. E.; ShamamandriMarkandaiah, S.; Han, J.; Philp, N. J.; Welebob, E.; Haeusler, A.; Pasinelli, P.; Manfredi, G.; Kawamata, H.

doi:10.1101/2023.06.07.544100

bioRxiv · 10.1101/2023.06.07.544100

Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes

Trotti, D.·Nelson, A. T.·Cicardi, M. E.·ShamamandriMarkandaiah, S.·Han, J.·Philp, N. J.·Welebob, E.·Haeusler, A.·Pasinelli, P.·Manfredi, G.·Kawamata, H.

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Abstract

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, although its potential role in disease pathogenesis is unknown. Here, we identified alterations in glucose metabolic pathways and ATP levels in the brain of asymptomatic C9-BAC mice. We found 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 found that one of the arginine-rich DPRs (PR) can directly contribute to glucose metabolism and metabolic stress. These findings provide a mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and support a feedforward loop model that opens several opportunities for therapeutic intervention.

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Trotti, D., Nelson, A. T., Cicardi, M. E., ShamamandriMarkandaiah, S., Han, J., Philp, N. J., Welebob, E., Haeusler, A., Pasinelli, P., Manfredi, G., Kawamata, H.. 2023-06-07. Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes. https://doi.org/10.1101/2023.06.07.544100

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