Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression.

Abstract

BACKGROUND:

Many neurodegenerative diseases are associated with protein misfolding/aggregation. Treatments mitigating the effects of such common pathological processes, rather than disease-specific symptoms, therefore have general therapeutic potential.

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.

• 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)

Chemical References

• Caenorhabditis elegans Proteins
• Forkhead Transcription Factors
• Transcription Factors
• daf-16 protein, C elegans
• Ethosuximide

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)