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

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

Affiliations

  • 1 Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. Xi.Chen@vai.org.
  • 2 Present Address: Centre for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI, 49503, USA. Xi.Chen@vai.org.
  • 3 Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. h.v.mccue@liverpool.ac.uk.
  • 4 Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. wongsq@liverpool.ac.uk.
  • 5 Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. sudhanvakashyap@gmail.com.
  • 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. kraemerb@uw.edu.
  • 7 Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. barclayj@liverpool.ac.uk.
  • 8 Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. burgoyne@liverpool.ac.uk.
  • 9 Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. amorgan@liverpool.ac.uk.
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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