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

Abstract

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.

Caenorhabditis elegans models of tauopathy

“…These effects were attributed to the inhibition of dopamine 2-like receptor-mediated signaling, as elimination of the dopamine 2-like receptor in Tau V337M worms produces similar neuroprotective effects (104). In a recent study, the antiepileptic drug ethosuximide increased the lifespan and partially corrected the Unc phenotype in Tau V337M worms with the effect dependent on the insulinsignaling pathway (106).…”

Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases

“…Azaperone, in particular, effectively ameliorated mutant Tau-induced functional defects and reduced the level of insoluble Tau aggregation [ 37 ]. Finally, a recent study reported that the anti-epileptic drug, ethosuximide, could ameliorate the impaired motility and reduced lifespan phenotypes of the Tau V337 M worm FTDP-17 model [ 38 ]. Interestingly, ethosuximide’s action in this worm Tau model was independent of its main proposed target in epilepsy, the T-type calcium channel.…”

Identifying Longevity Associated Genes by Integrating Gene Expression and Curated Annotations

“…HIL-7 (Histone H1 Like) gene expression may be associated with Ethosuximide treatment, a drug that increases worm lifespan and affects DAF-16/FOXO target gene expression (X. Chen et al, 2015). TTH-1 (Thymosin beta) is significantly increased in daf-2 mutants, which are very long-lived, suggesting possible pro-longevity status by association (Narayan et al, 2016).…”