title: Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression.
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.
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. Xi.Chen@vai.org.|Present Address: Centre for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI, 49503, USA. Xi.Chen@vai.org.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Hannah V
authors.initials: HV
authors.lastname: McCue
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. wongsq@liverpool.ac.uk.
authors.forename: Shi Quan
authors.initials: SQ
authors.lastname: Wong
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. sudhanvakashyap@gmail.com.
authors.forename: Sudhanva S
authors.initials: SS
authors.lastname: Kashyap
authors.affiliation: 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.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Kraemer
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. barclayj@liverpool.ac.uk.
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Barclay
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. burgoyne@liverpool.ac.uk.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burgoyne
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown St, Liverpool, L69 3BX, UK. amorgan@liverpool.ac.uk.
authors.forename: Alan
authors.initials: A
authors.lastname: Morgan
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005013:Ethosuximide / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D005013:Ethosuximide