論文 - 詳細
RRC ID | 36066 |
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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 |