Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes
Abstract
The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)nnucleotide repeat expansion (NRE) occurring in the first intron of theC9orf72gene (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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 07, 2023
- Source ID
- 10.1101/2023.06.07.544100
Entities
People
- A.t. Nelson
- Aaron Haeusler
- Davide Trotti
- E. Welebob
- Giovanni Manfredi
- Hibiki Kawamata
- Jinchen Han
- Maria Elena Cicardi
- N. Philp
- P. Pasinelli
- S.s. Markandaiah