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

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-epilepti...

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Autores principales: Chen, Xi, McCueF, Hannah V., Wong, Shi Quan, Kashyap, Sudhanva S., Kraemer, Brian C., Barclay, Jeff W., Burgoyne, Robert D., Morgan, Alan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587861/
https://www.ncbi.nlm.nih.gov/pubmed/26419537
http://dx.doi.org/10.1186/s13024-015-0046-3
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author Chen, Xi
McCueF, Hannah V.
Wong, Shi Quan
Kashyap, Sudhanva S.
Kraemer, Brian C.
Barclay, Jeff W.
Burgoyne, Robert D.
Morgan, Alan
author_facet Chen, Xi
McCueF, Hannah V.
Wong, Shi Quan
Kashyap, Sudhanva S.
Kraemer, Brian C.
Barclay, Jeff W.
Burgoyne, Robert D.
Morgan, Alan
author_sort Chen, Xi
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-015-0046-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-45878612015-09-30 Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression Chen, Xi McCueF, Hannah V. Wong, Shi Quan Kashyap, Sudhanva S. Kraemer, Brian C. Barclay, Jeff W. Burgoyne, Robert D. Morgan, Alan Mol Neurodegener Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-015-0046-3) contains supplementary material, which is available to authorized users. BioMed Central 2015-09-29 /pmc/articles/PMC4587861/ /pubmed/26419537 http://dx.doi.org/10.1186/s13024-015-0046-3 Text en © Chen et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Chen, Xi
McCueF, Hannah V.
Wong, Shi Quan
Kashyap, Sudhanva S.
Kraemer, Brian C.
Barclay, Jeff W.
Burgoyne, Robert D.
Morgan, Alan
Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression
title Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression
title_full Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression
title_fullStr Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression
title_full_unstemmed Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression
title_short Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression
title_sort ethosuximide ameliorates neurodegenerative disease phenotypes by modulating daf-16/foxo target gene expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587861/
https://www.ncbi.nlm.nih.gov/pubmed/26419537
http://dx.doi.org/10.1186/s13024-015-0046-3
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