Chen, Xi, McCuef, Hannah V, Wong, Shi Quan, Kashyap, Sudhanva S, Kraemer, Brian C, Barclay, Jeff W, Burgoyne, Robert D ORCID: 0000-0002-9219-0387 and Morgan, Alan ORCID: 0000-0002-0346-1289
(2015)
Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression.
Molecular Neurodegeneration, 10 (1).
51-.
Text
Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression.pdf - Unspecified Download (2MB) |
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.
Item Type: | Article |
---|---|
Uncontrolled Keywords: | Adult onset neuronal lipofuscinosis, Frontotemporal dementia, Neurodegeneration, Aging, Caenorhabditis elegans, Neuroblastoma |
Depositing User: | Symplectic Admin |
Date Deposited: | 11 Apr 2016 14:17 |
Last Modified: | 16 Dec 2022 16:03 |
DOI: | 10.1186/s13024-015-0046-3 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3000235 |