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BackgroundMany 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.ResultsHere 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0046-3) contains supplementary material, which is available to authorized users.

HighlightsWorms with mutant GABAA receptors exhibit convulsions upon exposure to pentylenetetrazol.Convulsions are prevented by the approved anti-epileptic drug, ethosuximide.C. elegans model is a higher throughput, ethical alternative to rodent seizure models.

Graphical abstractCRMs activate Nrf2, but inhibit NF-κB, and GSH depletion without covalent modification activates both Nrf2 and NF-κB. This leads to cellular protection against the potentially harmful effects of redox perturbation.