ArticleBrain : a journal of neurology2019
C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis.
Article in Brain : a journal of neurology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 89 citations in OpenAlex.
- Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons.Nature neuroscience · 2026Article
- Review
- TDP-43 impairs glycolysis by sequestering hexokinase 1 in amyotrophic lateral sclerosis.Acta neuropathologica · 2026Article
- Hypothesis-free evaluation of circulating metabolome provides cell-specific insights regarding the role of energy substrate availability in amyotrophic lateral sclerosis.BMC medicine · 2026Article
- C9orf72 in myeloid cells prevents an inflammatory response to microbial glycogen.Cell reports · 2026Article
- Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration inInternational journal of molecular sciences · 2026Article
- Disrupted astrocyte-neuron metabolic coupling in amyotrophic lateral sclerosis.Frontiers in cell and developmental biology · 2026Review
- Article
- The mCells · 2025Review
- C9orf72 hexanucleotide repeat expansions impair microglial response in ALS.Nature neuroscience · 2025Article
- Investigating the ageing-Parkinson's disease nexus: standardisation of in vitro models and techniques by the PD-AGE network.NPJ Parkinson's disease · 2025Review
- Article
- Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer's disease astrocytes.Molecular psychiatry · 2025Article
- Aberrant protein aggregation in amyotrophic lateral sclerosis.Journal of neurology · 2024Review
- Non-motor symptoms in patients with amyotrophic lateral sclerosis: current state and future directions.Journal of neurology · 2024Review
- Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits.Molecular neurodegeneration · 2024Article
- Glycogen accumulation modulates life span in a mouse model of amyotrophic lateral sclerosis.Journal of neurochemistry · 2024Article
- Glucose hypometabolism prompts RAN translation and exacerbates C9orf72-related ALS/FTD phenotypes.EMBO reports · 2024Article
- Astrocytes: The Stars in Neurodegeneration?Biomolecules · 2024Review
- The Inflammatory Puzzle: Piecing together the Links between Neuroinflammation and Amyotrophic Lateral Sclerosis.Aging and disease · 2024Review
4 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 2 institutions in 1 country.
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Abstract
It is important to understand how the disease process affects the metabolic pathways in amyotrophic lateral sclerosis and whether these pathways can be manipulated to ameliorate disease progression. To analyse the basis of the metabolic defect in amyotrophic lateral sclerosis we used a phenotypic metabolic profiling approach. Using fibroblasts and reprogrammed induced astrocytes from C9orf72 and sporadic amyotrophic lateral sclerosis cases we measured the production rate of reduced nicotinamide adenine dinucleotides (NADH) from 91 potential energy substrates simultaneously. Our screening approach identified that C9orf72 and sporadic amyotrophic lateral sclerosis induced astrocytes have distinct metabolic profiles compared to controls and displayed a loss of metabolic flexibility that was not observed in fibroblast models. This loss of metabolic flexibility, involving defects in adenosine, fructose and glycogen metabolism, as well as disruptions in the membrane transport of mitochondrial specific energy substrates, contributed to increased starvation induced toxicity in C9orf72 induced astrocytes. A reduction in glycogen metabolism was attributed to loss of glycogen phosphorylase and phosphoglucomutase at the protein level in both C9orf72 induced astrocytes and induced neurons. In addition, we found alterations in the levels of fructose metabolism enzymes and a reduction in the methylglyoxal removal enzyme GLO1 in both C9orf72 and sporadic models of disease. Our data show that metabolic flexibility is important in the CNS in times of bioenergetic stress.
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