ER Stress Induced by Tunicamycin Triggers α-Synuclein Oligomerization, Dopaminergic Neurons Death and Locomotor Impairment: a New Model of Parkinson's Disease
ER Stress Induced by Tunicamycin Triggers α-Synuclein Oligomerization, Dopaminergic Neurons Death and Locomotor Impairment: a New Model of Parkinson's Disease
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DOI：
10.1007/s12035-016-0114-x
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发表时间：
2017-10-01
影响因子：
5.1
通讯作者：
Zanata, Silvio M.
中科院分区：
文献类型：
--
作者：
Coppola-Segovia, Valentin;Cavarsan, Clarissa;Zanata, Silvio M.
帕金森病（Parkinson's disease，PD）是一种以黑质多巴胺能神经元的进行性死亡为特征的神经退行性疾病，其主要临床表现为帕金森病（Parkinson's disease，PD）。虽然PD的病因尚不清楚，但α-突触核蛋白聚集在PD发病机制中起关键作用，其可能与一些病理过程如氧化应激、内质网（ER）应激、蛋白质降解受损和线粒体功能障碍相关。越来越多的实验证据表明，ER应激参与PD，然而，大多数所描述的结果采用培养的细胞系和遗传修饰的动物模型。在这项研究中，我们开发了一种新的ER应激大鼠模型采用著名的ER应激因子衣霉素（Tm）。为了评估ER应激是否能够诱导PD特征，我们进行了Tm（0.1 μ g/大脑半球）的黑质内注射，并在注射后7天分析动物（雄性Wistar大鼠）。经典的6-OHDA神经毒素模型（1 μ g/大脑半球）用作PD的已建立阳性对照。我们发现，Tm注射诱导运动障碍，多巴胺能神经元死亡，和星形胶质细胞的激活。此外，我们观察到广泛的α-突触核蛋白寡聚化在SNPC的Tm注射的动物相比，DMSO注射的控制。最后，Tm和6-OHDA处理的动物都呈现出ER应激标志物水平的增加。总之，这些研究结果首次表明，ER应激Tm概括了在啮齿动物PD模型中观察到的一些表型特征，加强了ER应激可能是PD病理生理学的重要贡献者的概念。因此，我们建议黑质内注射Tm作为一种新的ER应激为基础的模型，在体内研究PD。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive death of dopaminergic neurons of the substantia nigra pars compacta (SNpc), leading to the major clinical abnormalities that characterize this disease. Although PD's etiology is unknown, a-synuclein aggregation plays a pivotal role in PD pathogenesis, which could be associated to some pathological processes such as oxidative stress, endoplasmic reticulum (ER) stress, impaired protein degradation, and mitochondrial dysfunction. Increasing experimental evidence indicates that ER stress is involved in PD, however most of the described results employed cultured cell lines and genetically modified animal models. In this study, we developed a new ER stress rat model employing the well-known ER stressor tunicamycin (Tm). To evaluate if ER stress was able to induce PD features, we performed an intranigral injection of Tm (0.1 mu g/cerebral hemisphere) and animals (male Wistar rats) were analyzed 7 days post injection. The classical 6-OHDA neurotoxin model (1 mu g/cerebral hemisphere) was used as an established positive control for PD. We show that Tm injection induced locomotor impairment, dopaminergic neurons death, and activation of astroglia. In addition, we observed an extensive a-synuclein oligomerization in SNpc of Tm-injected animals when compared with DMSO-injected controls. Finally, both Tm and 6-OHDA treated animals presented increased levels of ER stress markers. Taken together, these findings show for the first time that the ER stressor Tm recapitulates some of the phenotypic characteristics observed in rodent models of PD, reinforcing the concept that ER stress could be an important contributor to the pathophysiology of PD. Therefore, we propose the intranigral Tm injection as a new ER stress-based model for the study of PD in vivo.