Abstract | BACKGROUND: RESULTS: Here we report that the anti-epileptic drug ethosuximide rescues the short lifespan and chemosensory defects exhibited by C. elegans null mutants of dnj-14, the worm orthologue of the DNAJC5 gene mutated in autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. It also ameliorates the locomotion impairment and short lifespan of worms expressing a human Tau mutant that causes frontotemporal dementia. Transcriptomic analysis revealed a highly significant up-regulation of DAF-16/FOXO target genes in response to ethosuximide; and indeed RNAi knockdown of daf-16 abolished the therapeutic effect of ethosuximide in the worm dnj-14 model. Importantly, ethosuximide also increased the expression of classical FOXO target genes and reduced protein aggregation in mammalian neuronal cells. CONCLUSIONS: We have revealed a conserved neuroprotective mechanism of action of ethosuximide from worms to mammalian neurons. Future experiments in mouse neurodegeneration models will be important to confirm the repurposing potential of this well-established anti-epileptic drug for treatment of human neurodegenerative diseases.
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Authors | Xi Chen, Hannah V McCue, Shi Quan Wong, Sudhanva S Kashyap, Brian C Kraemer, Jeff W Barclay, Robert D Burgoyne, Alan Morgan |
Journal | Molecular neurodegeneration
(Mol Neurodegener)
Vol. 10
Pg. 51
(Sep 29 2015)
ISSN: 1750-1326 [Electronic] England |
PMID | 26419537
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Caenorhabditis elegans Proteins
- Forkhead Transcription Factors
- Transcription Factors
- daf-16 protein, C elegans
- Ethosuximide
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Topics |
- Animals
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
(genetics)
- Disease Models, Animal
- Ethosuximide
(pharmacology)
- Forkhead Transcription Factors
(genetics)
- Gene Expression
(drug effects)
- Mutation
(genetics)
- Phenotype
- Signal Transduction
(drug effects)
- Transcription Factors
(metabolism)
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