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Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression.
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2015-09-29 , DOI: 10.1186/s13024-015-0046-3
Xi Chen 1, 2 , Hannah V McCue 1 , Shi Quan Wong 1 , Sudhanva S Kashyap 1 , Brian C Kraemer 3 , Jeff W Barclay 1 , Robert D Burgoyne 1 , Alan Morgan 1
Affiliation  

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.

中文翻译:


Ethosuximide 通过调节 DAF-16/FOXO 靶基因表达来改善神经退行性疾病表型。



背景技术许多神经退行性疾病与蛋白质错误折叠/聚集有关。因此,减轻这种常见病理过程的影响而不是疾病特异性症状的治疗具有普遍的治疗潜力。结果在此,我们报告抗癫痫药物乙舒酰亚胺可以挽救线虫dnj-14无效突变体所表现出的短寿命和化学感应缺陷,dnj-14是常染色体显性成人发病的神经元蜡质脂褐质沉着症中DNAJC5基因突变的蠕虫直系同源物。它还可以改善表达人类 Tau 突变体(导致额颞叶痴呆)的蠕虫的运动障碍和短寿命。转录组分析显示,乙舒酰亚胺对 DAF-16/FOXO 靶基因的显着上调;事实上,daf-16 的 RNAi 敲低消除了 ethosuximide 在 dnj-14 蠕虫模型中的治疗效果。重要的是,ethosuximide 还增加了经典 FOXO 靶基因的表达并减少了哺乳动物神经元细胞中的蛋白质聚集。结论 我们揭示了乙磺酰亚胺对线虫对哺乳动物神经元的保守神经保护作用机制。未来在小鼠神经退行性疾病模型中进行的实验对于确认这种成熟的抗癫痫药物治疗人类神经退行性疾病的重新利用潜力非常重要。
更新日期:2019-11-01
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