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

  • Mol Neurodegener. 2015 Sep 29;10:51. doi: 10.1186/s13024-015-0046-3.
Xi Chen  1  2 ,  Hannah V McCue  3 ,  Shi Quan Wong  4 ,  Sudhanva S Kashyap  5 ,  Brian C Kraemer  6 ,  Jeff W Barclay  7 ,  Robert D Burgoyne  8 ,  Alan Morgan  9
Affiliations
  • 1. Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. [email protected].
  • 2. Present Address: Centre for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI, 49503, USA. [email protected].
  • 3. Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. [email protected].
  • 4. Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. [email protected].
  • 5. Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. [email protected].
  • 6. Geriatrics Research Education and Clinical Center, Seattle Veterans Affairs Puget Sound Health Care System and University of Washington Department of Medicine, 1660 South Columbian Way, Seattle, WA, 98108, USA. [email protected].
  • 7. Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. [email protected].
  • 8. Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. [email protected].
  • 9. Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. [email protected].
PMID: 26419537 DOI: 10.1186/s13024-015-0046-3
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.

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