Medium-Chain Fatty Acids Rescue Motor Function and Neuromuscular Junction Degeneration in a Drosophila Model of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterised by progressive degeneration of the motor neurones. An expanded GGGGCC (G4C2) hexanucleotide repeat in C9orf72 is the most common genetic cause of ALS and frontotemporal dementia (FTD); therefore, the result...

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Published in:Cells (Basel, Switzerland) Switzerland), 2023-08, Vol.12 (17), p.2163
Main Authors: Dunn, Ella, Steinert, Joern R., Stone, Aelfwin, Sahota, Virender, Williams, Robin S. B., Snowden, Stuart, Augustin, Hrvoje
Format: Article
Language:English
Subjects:
4-MOA
ALS
Alzheimer's disease
Amyotrophic lateral sclerosis
Convulsions & seizures
Dementia disorders
Drosophila
Epilepsy
Fatty acids
Food
Frontotemporal dementia
Glutamic acid receptors
Insects
Larvae
MCFA
Metabolic pathways
Metabolism
Morphology
motor function
Nervous system
Neurodegeneration
Neurodegenerative diseases
Neuromuscular junctions
Physiology
Postsynaptic density
Receptor density
Silicones
Therapeutic targets
Walking
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Summary:Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterised by progressive degeneration of the motor neurones. An expanded GGGGCC (G4C2) hexanucleotide repeat in C9orf72 is the most common genetic cause of ALS and frontotemporal dementia (FTD); therefore, the resulting disease is known as C9ALS/FTD. Here, we employ a Drosophila melanogaster model of C9ALS/FTD (C9 model) to investigate a role for specific medium-chain fatty acids (MCFAs) in reversing pathogenic outcomes. Drosophila larvae overexpressing the ALS-associated dipeptide repeats (DPRs) in the nervous system exhibit reduced motor function and neuromuscular junction (NMJ) defects. We show that two MCFAs, nonanoic acid (NA) and 4-methyloctanoic acid (4-MOA), can ameliorate impaired motor function in C9 larvae and improve NMJ degeneration, although their mechanisms of action are not identical. NA modified postsynaptic glutamate receptor density, whereas 4-MOA restored defects in the presynaptic vesicular release. We also demonstrate the effects of NA and 4-MOA on metabolism in C9 larvae and implicate various metabolic pathways as dysregulated in our ALS model. Our findings pave the way to identifying novel therapeutic targets and potential treatments for ALS.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells12172163