Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models
Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models
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DOI：
10.1242/dmm.004267
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发表时间：
2010-03-01
影响因子：
4.3
通讯作者：
Lindquist, Susan
中科院分区：
文献类型：
--
作者：
Su, Linhui Julie;Auluck, Pavan K.;Lindquist, Susan
α -突触核蛋白（α -syn）是一种参与囊泡运输的小脂质结合蛋白，其功能尚不清楚。由于α -syn功能障碍与包括帕金森病（PD）在内的多种神经退行性疾病有关，因此引起了人类生物学和医学的极大兴趣。我们之前创建了一个α -syn病理生物学的酵母模型，该模型建立了一个对α -syn表达特别敏感的囊泡运输过程。我们还发现了一组核心蛋白，它们具有与α -syn毒性相关的多种活性，从酵母到哺乳动物神经元都是保守的。在这里，我们报告了一种表达更高水平α -syn的酵母菌株在线粒体中也表现出强烈的缺陷！函数。与我们之前的菌株不同，遗传抑制内质网（ER）到高尔基体的运输并不会抑制该菌株的α -syn毒性。为了找出能够同时挽救α -syn的这些明显不同的病理作用的单个化合物，我们筛选了115,000个化合物库。我们发现了一类小分子，在这种高毒性菌株的微摩尔浓度下降低α -syn毒性。这些化合物减少了α -syn病灶的形成，重建了er到高尔基体的运输，并改善了α -syn介导的线粒体损伤。他们还纠正了α -syn在线虫神经元和大鼠初级神经元中脑培养中的毒性。值得注意的是，这些化合物还保护神经元免受鱼藤酮诱导的毒性，这已被用于模拟与人类帕金森病相关的线粒体缺陷。单个化合物能够挽救酵母和神经元中α -syn的多种毒性，这表明它们作用于将这些毒性联系起来的根深蒂固的生物过程，并且已经在真核生物进化中保存了10亿年。因此，开发新的治疗策略以同时针对PD的多种病理特征似乎是可能的。
alpha-Synuclein (alpha-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created a yeast model of alpha-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to alpha-syn expression. We also uncovered a core group of proteins with diverse activities related to alpha-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of alpha-syn also exhibits strong defects in mitochondria! function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress alpha-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of alpha-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced alpha-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of alpha-syn foci, re-established ER-to-Golgi trafficking and ameliorated alpha-syn-mediated damage to mitochondria. They also corrected the toxicity of alpha-syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of alpha-syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD.