Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression.
Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression.
复制标题
DOI：
10.1186/s13024-015-0046-3
复制
发表时间：
2015-09-29
影响因子：
15.1
通讯作者：
Morgan A
中科院分区：
文献类型：
--
作者：
Chen X;McCue HV;Wong SQ;Kashyap SS;Kraemer BC;Barclay JW;Burgoyne RD;Morgan A
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. 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. 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. The online version of this article (doi:10.1186/s13024-015-0046-3) contains supplementary material, which is available to authorized users.
影响因子：
3.7
作者：
Choi H;Schneider H;Klum S;Chandler-Brown D;Kaeberlein M;Shamieh L
通讯作者：
Shamieh L