Glucose hypometabolism prompts RAN translation and exacerbates C9orf72-related ALS/FTD phenotypes.
EMBO Rep
; 25(5): 2479-2510, 2024 May.
Article
en En
| MEDLINE
| ID: mdl-38684907
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, 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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Fenotipo
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Proteína de Unión al GTP ran
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Demencia Frontotemporal
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Proteína C9orf72
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Glucosa
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Esclerosis Amiotrófica Lateral
Límite:
Animals
Idioma:
En
Revista:
EMBO Rep
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EMBO rep
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EMBO reports
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos