Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity
Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity
复制标题
DOI：
10.1093/hmg/dds190
复制
发表时间：
2012-08-15
影响因子：
3.5
通讯作者：
Baumeister, Ralf
中科院分区：
文献类型：
--
作者：
Fatouros, Chronis;Pir, Ghulam Jeelani;Baumeister, Ralf
增加的Tau蛋白淀粉样蛋白原性已经在几种神经退行性疾病（统称为tau蛋白病）中有因果关系。在病理条件下，Tau变得过度磷酸化并形成细胞内聚集体。K280的缺失，这是一种突变，通常出现在与17号染色体相关的帕金森氏症的额颞叶痴呆患者中，增强了Tau聚集倾向（促聚集）。相反，I277 P和I308 P突变的引入防止了-片层形成和随后的聚集（抗聚集）。在这项研究中，我们通过在秀丽隐杆线虫的神经系统中表达亲或抗聚集体Tau种类来创建Tau病模型。表达高度淀粉样蛋白生成性Tau种类的动物显示加速的Tau聚集和表现为严重受损的运动性和明显的神经元功能障碍的病理学。此外，我们观察到，在这些动物的线粒体轴突运输受到干扰。表达抗聚集剂组合的对照动物具有相当温和的表型。我们随后测试了几种Tau聚集抑制剂化合物并观察到Tau蛋白毒性的减轻。特别是，一种穿过哺乳动物血脑屏障的新型化合物被证明有效改善运动性以及延迟神经元缺陷的积累。我们的研究建立了一个新的C.这一结果证实了Tau聚集介导的毒性的elegans模型，并支持了抑制Tau聚集的成核可以是神经保护性的新兴概念。
Increased Tau protein amyloidogenicity has been causatively implicated in several neurodegenerative diseases, collectively called tauopathies. In pathological conditions, Tau becomes hyperphosphorylated and forms intracellular aggregates. The deletion of K280, which is a mutation that commonly appears in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17, enhances Tau aggregation propensity (pro-aggregation). In contrast, introduction of the I277P and I308P mutations prevents -sheet formation and subsequent aggregation (anti-aggregation). In this study, we created a tauopathy model by expressing pro- or anti-aggregant Tau species in the nervous system of Caenorhabditis elegans. Animals expressing the highly amyloidogenic Tau species showed accelerated Tau aggregation and pathology manifested by severely impaired motility and evident neuronal dysfunction. In addition, we observed that the axonal transport of mitochondria was perturbed in these animals. Control animals expressing the anti-aggregant combination had rather mild phenotype. We subsequently tested several Tau aggregation inhibitor compounds and observed a mitigation of Tau proteotoxicity. In particular, a novel compound that crosses the bloodbrain barrier of mammals proved effective in ameliorating the motility as well as delaying the accumulation of neuronal defects. Our study establishes a new C. elegans model of Tau aggregation-mediated toxicity and supports the emerging notion that inhibiting the nucleation of Tau aggregation can be neuroprotective.