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

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.

• Publication year

  2015

• Venue

  Molecular Neurodegeneration

• Publication date

  2015-09-29

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/s13024-015-0046-3PMID 26419537PMCID 4587861
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2015cited by this paper
• Drug repositioning in Alzheimer's disease.

  2015cited by this paper
• Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol

  2014cited by this paper
• FOXO3 determines the accumulation of α-synuclein and controls the fate of dopaminergic neurons in the substantia nigra.

  2014cited by this paper
• Phenotypic Screens Targeting Neurodegenerative Diseases

  2014cited by this paper
• Combating neurodegenerative disease with chemical probes and model systems.

  2014cited by this paper
• A systematic analysis of protein palmitoylation in Caenorhabditis elegans

  2014cited by this paper
• Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease

  2013cited by this paper
• Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity.

  2013cited by this paper
• Evaluation of longevity enhancing compounds against transactive response DNA-binding protein-43 neuronal toxicity.

  2013cited by this paper
• Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism

  2013cited by this paper
• UV-Photoconversion of Ethosuximide from a Longevity-Promoting Compound to a Potent Toxin

  2013cited by this paper
• Alzheimer's disease drug discovery: in vivo screening using Caenorhabditis elegans as a model for β-amyloid peptide-induced toxicity.

  2013cited by this paper
• PQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity.

  2013cited by this paper
• Induction of Neuronal Differentiation of Rat Muscle-Derived Stem Cells in Vitro Using Basic Fibroblast Growth Factor and Ethosuximide

  2013cited by this paper
• PolyQ proteins interfere with nuclear degradation of cytosolic proteins by sequestering the Sis1p chaperone.

  2013cited by this paper
• Proteasome Inhibition Alleviates SNARE-Dependent Neurodegeneration

  2012cited by this paper
• Selection of Reliable Reference Genes in Caenorhabditis elegans for Analysis of Nanotoxicity

  2012cited by this paper
• Mutations in the Gene DNAJC5 Cause Autosomal Dominant Kufs Disease in a Proportion of Cases: Study of the Parry Family and 8 Other Families

  2012cited by this paper
• Drug repositioning for Alzheimer's disease

  2012cited by this paper
• Identification of common genetic modifiers of neurodegenerative diseases from an integrative analysis of diverse genetic screens in model organisms

  2012cited by this paper
• A novel Caenorhabditis elegans allele, smn-1(cb131), mimicking a mild form of spinal muscular atrophy, provides a convenient drug screening platform highlighting new and pre-approved compounds.

  2011cited by this paper
• Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.

  2011cited by this paper
• CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity

  2011cited by this paper
• Watching worms whither: modeling neurodegeneration in C. elegans.

  2011cited by this paper
• TDP-43 neurotoxicity and protein aggregation modulated by heat shock factor and insulin/IGF-1 signaling.

  2011cited by this paper
• Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis

  2011cited by this paper
• CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity

  2011cited by this paper
• Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets

  2011cited by this paper
• Neuron Dysfunction Is Induced by Prion Protein with an Insertional Mutation via a Fyn Kinase and Reversed by Sirtuin Activation in Caenorhabditis elegans

  2010cited by this paper
• Chaperoning the SNAREs: a role in preventing neurodegeneration?

  2010cited by this paper
• Neurodegenerative diseases: Lessons from genome-wide screens in small model organisms

  2009cited by this paper
• FOXO3a Is Broadly Neuroprotective In Vitro and In Vivo against Insults Implicated in Motor Neuron Diseases

  2009cited by this paper
• Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease.

  2009cited by this paper
• Reduced IGF-1 signaling delays age-associated proteotoxicity in mice.

  2009cited by this paper
• The Anticonvulsant Ethosuximide Disrupts Sensory Function to Extend C. elegans Lifespan

  2008cited by this paper
• FoxO transcription factors in the maintenance of cellular homeostasis during aging.

  2008cited by this paper
• Identification of Potential Therapeutic Drugs for Huntington's Disease using Caenorhabditis elegans

  2007cited by this paper
• Ethosuximide: from bench to bedside.

  2007influential reference
• Opposing Activities Protect Against Age-Onset Proteotoxicity

  2006cited by this paper
• The C. elegans T-type calcium channel CCA-1 boosts neuromuscular transmission

  2005cited by this paper
• Anticonvulsant Medications Extend Worm Life-Span

  2005cited by this paper
• Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons

  2005cited by this paper
• The Synaptic Vesicle Protein CSPα Prevents Presynaptic Degeneration

  2004cited by this paper
• The synaptic vesicle protein CSP alpha prevents presynaptic degeneration.

  2004cited by this paper
• Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

  2003influential reference
• Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans

  2003cited by this paper
• Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress

  2002cited by this paper
• Block of Thalamic T-Type Ca2+ Channels by Ethosuximide Is Not the Whole Story

  2002cited by this paper
• The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans

  2002cited by this paper
• daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans.

  2001cited by this paper
• C. elegans: a novel pharmacogenetic model to study Parkinson's disease.

  2001cited by this paper
• Cysteine‐String Protein

  2000cited by this paper
• Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans.

  2000cited by this paper
• Defining wild-type life span in Caenorhabditis elegans.

  2000cited by this paper
• Neurobiology of the Caenorhabditis elegans genome.

  1998cited by this paper
• Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans.

  1995cited by this paper
• Controlling the false discovery rate: a practical and powerful approach to multiple testing

  1995cited by this paper
• Paralysis and early death in cysteine string protein mutants of Drosophila.

  1994cited by this paper
• Molecular Neurodegeneration

  year unknowncited by this paper

• Unlocking neuronal health: leveraging C. elegans for drug repurposing studies

  2026cites this paper
• TDP‐43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models

  2025cites this paper
• Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43 toxicity.

  2024cites this paper
• CYP14 family in Caenorhabditis elegans: Mitochondrial function, detoxification, and lifespan

  2024cites this paper
• Tissue distribution of cysteine string protein/DNAJC5 in C. elegans analysed by CRISPR/Cas9-mediated tagging of endogenous DNJ-14

  2024cites this paper
• Why do we age? questions and answers in regenerative medicine

  2024cites this paper
• Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43-toxicity

  2024cites this paper
• Can gene expression delay aging and increase longevity?

  2023cites this paper
• A Dual-Functional Probe that Allows Cascade Response to Hydrogen Peroxide Oxidative Stress-Induced Protein Aggregation in Live Cells

  2023cites this paper
• Identifying the intervention mechanisms of o-methoxycinnamic acid in hyperuricemia model by using UPLC-Q-TOF/MS spectroscopy metabonomic approach

  2023cites this paper
• A Caenorhabditis elegans model of autosomal dominant adult-onset neuronal ceroid lipofuscinosis identifies ethosuximide as a potential therapeutic

  2022influential citation
• Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling

  2022cites this paper
• FOXO and related transcription factors binding elements in the regulation of neurodegenerative disorders.

  2021cites this paper
• Protective Effect of Ethosuximide against Glutamate-Induced Cytotoxicity and Oxidative Stress in C6 Glial Cells

  2021cites this paper
• C. elegans as a Potential Model for Acute Seizure-Like Activity

  2021cites this paper
• Cysteine String Proteins.

  2020cites this paper
• Identifying longevity associated genes by integrating gene expression and curated annotations

  2020cites this paper
• Bacteria metabolites from Peganum harmala L. polysaccharides inhibits polyQ aggregation through proteasome-mediated protein degradation in C. elegans.

  2020cites this paper
• Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation

  2020cites this paper
• Roles of Forkhead Box O (FoxO) Transcription Factors in Neurodegenerative Diseases: A panoramic view.

  2019cites this paper
• The contribution of multicellular model organisms to neuronal ceroid lipofuscinosis research.

  2019cites this paper
• Increased REST to Optimize Life Span?

  2019cites this paper
• The Caenorhabditis elegans cysteine-string protein homologue DNJ-14 is dispensable for neuromuscular junction maintenance across ageing

  2019cites this paper
• Regulation of Lifespan by Neural Excitation and REST

  2019cites this paper
• Analyzing the Synergistic Effects of Antioxidants in Combating Photoaging Using Model Nematode, Caenorhabditis elegans

  2019cites this paper
• A Caenorhabditis elegans assay of seizure-like activity optimised for identifying antiepileptic drugs and their mechanisms of action

  2018cites this paper
• Human amyloid β peptide and tau co-expression impairs behavior and causes specific gene expression changes in Caenorhabditis elegans.

  2018cites this paper
• α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy

  2018cites this paper
• Caenorhabditis elegans as a model system for target identification and drug screening against neurodegenerative diseases.

  2018cites this paper
• Diagnostic methods and emerging treatments for adult neuronal ceroid lipofuscinoses (Kufs disease)

  2017cites this paper
• Current Perspective in the Discovery of Anti-aging Agents from Natural Products

  2017cites this paper
• Toxicogenomics of iron oxide nanoparticles in the nematode C. elegans

  2017cites this paper
• Caenorhabditis elegans models of tauopathy

  2017cites this paper
• The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease

  2017cites this paper
• Dianxianning improved amyloid β-induced pathological characteristics partially through DAF-2/DAF-16 insulin like pathway in transgenic C. elegans

  2017cites this paper
• Real-time imaging of RGC death with a cell-impermeable nucleic acid dyeing compound after optic nerve crush in a murine model.

  2016cites this paper
• Erratum to: Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression

  2015cites this paper
• Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases

  2015cites this paper