Laboratory of Molecular Neurobiology and Neuroproteomics, Swiss Federal Institute of Technology Lausanne, SV-BMI-LMNN-AI2351, CH-1015 Lausanne, Switzerland.
Laboratory of Molecular Neurobiology and Neuroproteomics, Swiss Federal Institute of Technology Lausanne, SV-BMI-LMNN-AI2351, CH-1015 Lausanne, Switzerland; Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna Via Selmi, 3, 40126 Bologna, Italy.
J Biol Chem. 2010 May 14;285(20):14941-14954. doi: 10.1074/jbc.M109.080390. Epub 2010 Feb 11.
Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease (AD). There is considerable consensus that the increased production and/or aggregation of alpha-synuclein (alpha-syn) plays a central role in the pathogenesis of PD and related synucleinopathies. Current therapeutic strategies for treating PD offer mainly transient symptomatic relief and aim at the restitution of dopamine levels to counterbalance the loss of dopaminergic neurons. Therefore, the identification and development of drug-like molecules that block alpha-synuclein aggregation and prevent the loss of dopaminergic neurons are desperately needed to treat or slow the progression of PD. Here, we show that entacapone and tolcapone are potent inhibitors of alpha-syn and beta-amyloid (Abeta) oligomerization and fibrillogenesis, and they also protect against extracellular toxicity induced by the aggregation of both proteins. Comparison of the anti-aggregation properties of entacapone and tolcapone with the effect of five other catechol-containing compounds, dopamine, pyrogallol, gallic acid, caffeic acid, and quercetin on the oligomerization and fibrillization of alpha-syn and Abeta, demonstrate that the catechol moiety is essential for the anti-amyloidogenic activity. Our findings present the first characterization of the anti-amyloidogenic properties of tolcapone and entacapone against both alpha-synuclein and Abeta42 and highlight the potential of this class of nitro-catechol compounds as anti-amyloidogenic agents. Their inhibitory properties, mode of action, and structural properties suggest that they constitute promising lead compounds for further optimization.
帕金森病（PD）是仅次于阿尔茨海默病（AD）的第二大常见神经退行性疾病。人们普遍认为，α-突触核蛋白（α-syn）的产生和/或聚集增加在 PD 及相关突触核蛋白病的发病机制中起核心作用。目前治疗 PD 的策略主要提供短暂的症状缓解，并旨在恢复多巴胺水平，以抵消多巴胺能神经元的丧失。因此，迫切需要识别和开发能够阻止α-突触核蛋白聚集和防止多巴胺能神经元丧失的类药分子，以治疗或减缓 PD 的进展。在这里，我们表明恩他卡朋和托卡朋是α-突触核蛋白和β-淀粉样蛋白（Abeta）寡聚体和原纤维形成的有效抑制剂，它们还能防止这两种蛋白质聚集引起的细胞外毒性。将恩他卡朋和托卡朋的抗聚集特性与其他五种含有儿茶酚的化合物、多巴胺、焦儿茶酚、没食子酸、咖啡酸和槲皮素对α-突触核蛋白和 Abeta 寡聚体和原纤维形成的影响进行比较，表明儿茶酚部分对于抗淀粉样特性是必需的。我们的研究结果首次描述了托卡朋和恩他卡朋对α-突触核蛋白和 Abeta42 的抗淀粉样特性，并强调了这类硝基儿茶酚化合物作为抗淀粉样蛋白的潜在用途。它们的抑制特性、作用模式和结构特性表明，它们构成了进一步优化的有前途的先导化合物。
