RRC ID 36066
著者 Chen X, McCue HV, Wong SQ, Kashyap SS, Kraemer BC, Barclay JW, Burgoyne RD, Morgan A.
タイトル Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression.
ジャーナル Mol Neurodegener
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.
巻・号 10
ページ 51
公開日 2015-9-29
DOI 10.1186/s13024-015-0046-3
PII 10.1186/s13024-015-0046-3
PMID 26419537
PMC PMC4587861
MeSH Animals Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics* Disease Models, Animal Ethosuximide / pharmacology* Forkhead Transcription Factors / genetics* Gene Expression / drug effects* Mutation / genetics* Phenotype Signal Transduction / drug effects Transcription Factors / metabolism
IF 9.599
引用数 20
WOS 分野 NEUROSCIENCES
リソース情報
線虫 tm3223