Valproic acid ameliorates C. elegans dopaminergic neurodegeneration with implications for ERK-MAPK signaling.
Valproic acid ameliorates C. elegans dopaminergic neurodegeneration with implications for ERK-MAPK signaling.
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DOI：
10.1016/j.neulet.2013.02.026
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发表时间：
2013-04-29
影响因子：
2.5
通讯作者：
Caldwell GA
中科院分区：
文献类型：
--
作者：
Kautu BB;Carrasquilla A;Hicks ML;Caldwell KA;Caldwell GA
帕金森氏病(PD)是一种目前无法治愈的神经退行性疾病，影响着老龄化人口。黑质多巴胺能神经元的缺失是帕金森病的病理特征之一。帕金森病的确切原因仍未解决，但有证据支持环境和遗传因素。目前治疗帕金森病的努力是为了发现在阻止帕金森病患者年龄依赖性神经变性方面有希望的化合物。α-突触核蛋白(α-Syn)是一种人类蛋白，在家族性帕金森病患者的特定人群中发生突变。α-Syn在帕金森病动物模型中的过度表达复制了帕金森病的关键症状，包括神经变性。在这里，我们使用线虫线虫作为一个模型系统，其中α-Syn毒性导致多巴胺能神经变性，以测试丙戊酸(VA)对神经元的保护能力。我们的研究结果表明，用中等浓度的VA处理线虫可以显著保护多巴胺能神经元免受α-Syn的毒性。与先前建立的与VA在细胞中的机制作用有关的知识一致，我们通过遗传分析表明，VA所提供的神经保护作用受到细胞特异性缺失的线虫MAP细胞外信号调节激酶(ERK)同源蛋白MPK-1在多巴胺能神经元中的抑制。这些结果提示，VA可能通过ERK-MAPK发挥其神经保护作用，或者与MAPK信号通路共同作用，提供额外的多巴胺能神经保护作用。
Parkinson’s disease (PD) is a currently incurable neurodegenerative disorder that affects the aging population. The loss of dopaminergic neurons in the substantia nigra is one of the pathological features of PD. The precise causes of PD remain unresolved but evidence supports both environmental and genetic contributions. Current efforts for the treatment of PD are directed toward the discovery of compounds that show promise in impeding age-dependent neurodegeneration in PD patients. Alpha-synuclein (α-Syn) is a human protein that is mutated in specific populations of patients with familial PD. Overexpression of α-Syn in animal models of PD replicates key symptoms of PD, including neurodegeneration. Here, we use the nematode C. elegans as a model system, whereby α-Syn toxicity causes dopaminergic neurodegeneration, to test the capacity of valproic acid (VA) to protect neurons. The results of our study showed that treatment of nematodes with moderate concentrations of VA significantly protects dopaminergic neurons against α-Syn toxicity. Consistent with previously established knowledge related to the mechanistic action of VA in the cell, we showed through genetic analysis that the neuroprotection conferred by VA is inhibited by cell-specific depletion of the C. elegans ortholog of the MAP extracellular signal-regulated kinase (ERK), MPK-1, in the dopaminergic neurons. These findings suggest that VA may exert its neuroprotective effect via ERK-MAPK, or alternately could act with MAPK signaling to additively provide dopaminergic neuroprotection.
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