Department of Bioengineering and Therapeutic Sciences, Program of Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
PLoS One. 2012;7(4):e35645. doi: 10.1371/journal.pone.0035645. Epub 2012 Apr 26.
Parkinson's disease is a neurodegenerative disorder characterized by the prominent degeneration of dopaminergic (DA) neurons among other cell types. Here we report a first chemical screen of over 5,000 compounds in zebrafish, aimed at identifying small molecule modulators of DA neuron development or survival. We find that Neriifolin, a member of the cardiac glycoside family of compounds, impairs survival but not differentiation of both zebrafish and mammalian DA neurons. Cardiac glycosides are inhibitors of Na(+)/K(+) ATPase activity and widely used for treating heart disorders. Our data suggest that Neriifolin impairs DA neuronal survival by targeting the neuronal enriched Na(+)/K(+) ATPase α3 subunit (ATP1A3). Modulation of ionic homeostasis, knockdown of p53, or treatment with antioxidants protects DA neurons from Neriifolin-induced death. These results reveal a previously unknown effect of cardiac glycosides on DA neuronal survival and suggest that it is mediated through ATP1A3 inhibition, oxidative stress, and p53. They also elucidate potential approaches for counteracting the neurotoxicity of this valuable class of medications.
帕金森病是一种神经退行性疾病，其特征是多巴胺能（DA）神经元以及其他细胞类型的明显退化。在这里，我们报告了在斑马鱼中进行的超过 5000 种化合物的首次化学筛选，旨在鉴定小分子调节剂以调节 DA 神经元的发育或存活。我们发现，一种属于强心苷类化合物的 Neriifolin 会损害斑马鱼和哺乳动物 DA 神经元的存活，但不会损害其分化。强心苷是 Na(+)/K(+)ATP 酶活性的抑制剂，广泛用于治疗心脏疾病。我们的数据表明，Neriifolin 通过靶向神经元丰富的 Na(+)/K(+)ATP 酶α3 亚基（ATP1A3）来损害 DA 神经元的存活。离子动态平衡的调节、p53 的敲低或抗氧化剂的处理均可保护 DA 神经元免受 Neriifolin 诱导的死亡。这些结果揭示了强心苷对 DA 神经元存活的先前未知的影响，并表明它是通过 ATP1A3 抑制、氧化应激和 p53 介导的。它们还阐明了对抗这类有价值药物的神经毒性的潜在方法。
