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Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes
A T Nelson1, M E Cicardi1, S S Markandaiah1
1Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Biorxiv : the Preprint Server for Biology
|June 19, 2023
Summary
Glucose hypometabolism in C9orf72 gene expansions drives toxic protein production and neuronal dysfunction in amyotrophic lateral sclerosis and frontotemporal dementia, revealing a potential therapeutic target.
Area of Science:
- Neuroscience
- Genetics
- Metabolic pathways
Background:
- The C9orf72 gene (C9) repeat expansion is the primary genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- Brain glucose hypometabolism is a known characteristic of C9-NRE carriers, but its role in disease development is unclear.
Approach:
- Investigated glucose metabolism and ATP levels in asymptomatic C9-BAC mice.
- Examined the impact of glucose hypometabolism on dipeptide repeat protein (DPR) production and neuronal survival.
- Assessed the role of arginine-rich DPRs in metabolic stress.
Key Points:
- Glucose hypometabolism, via GCN2 kinase activation, promotes toxic DPR production.
- Impaired neuronal survival and motor dysfunction were observed in C9-BAC mice.
- Arginine-rich DPRs contribute to metabolic dysregulation.
Conclusions:
- Established a mechanistic link between energy imbalance and C9-ALS/FTD pathogenesis.
- Proposed a feedforward loop model for disease progression.
- Identified potential therapeutic targets for C9-ALS/FTD by addressing metabolic dysfunction.
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