A53T Human α-Synuclein Overexpression in Transgenic Mice Induces Pervasive Mitochondria Macroautophagy Defects Preceding Dopamine Neuron Degeneration
A53T Human α-Synuclein Overexpression in Transgenic Mice Induces Pervasive Mitochondria Macroautophagy Defects Preceding Dopamine Neuron Degeneration
复制标题
DOI：
10.1523/jneurosci.0089-14.2015
复制
发表时间：
2015-01-21
影响因子：
5.3
通讯作者：
Zhuang, Xiaoxi
中科院分区：
文献类型：
--
作者：
Chen, Linan;Xie, Zhiguo;Zhuang, Xiaoxi
体外证据表明，巨自噬对受损线粒体的低效清除会导致帕金森病 (PD)。使用组织特异性基因扩增策略，我们生成了一种转基因小鼠系，该小鼠系在多巴胺 (DA) 神经元中特异地过度表达人类 α-突触核蛋白 A53T。转基因小鼠表现出严重的早发性线粒体异常，其特征是巨自噬标记阳性的细胞质内含物主要含有线粒体残余物，这发生在 DA 神经元退化之前。这些转基因小鼠中 Parkin 或 PINK1 的基因缺失显着恶化了线粒体病理，包括内含物急剧增大和线粒体总含量的损失。这些数据表明线粒体是 α-突触核蛋白的主要靶标，其缺陷的自噬清除在发病机制中发挥着重要作用。此外，内源性 PINK1 或 Parkin 对于受损线粒体的正确自噬清除是必不可少的。我们的数据首次在基于已知 PD 遗传学的体内模型中建立了线粒体巨自噬损伤和 DA 神经元变性之间的重要联系。该模型、其明确的病理学以及本研究中主要发病机制的论证为未来的研究奠定了基础和重点方向。
In vitro evidence suggests that the inefficient removal of damaged mitochondria by macroautophagy contributes to Parkinson's disease (PD). Using a tissue-specific gene amplification strategy, we generated a transgenic mouse line with human alpha-synuclein A53T overexpression specifically in dopamine (DA) neurons. Transgenic mice showed profound early-onset mitochondria abnormalities, characterized by macroautophagy marker-positive cytoplasmic inclusions containing mainly mitochondrial remnants, which preceded the degeneration of DA neurons. Genetic deletion of either parkin or PINK1 in these transgenic mice significantly worsened mitochondrial pathologies, including drastically enlarged inclusions and loss of total mitochondria contents. These data suggest that mitochondria are the main targets of alpha-synuclein and their defective autophagic clearance plays a significant role during pathogenesis. Moreover, endogenous PINK1 or parkin is indispensable for the proper autophagic removal of damaged mitochondria. Our data for the first time establish an essential link between mitochondria macroautophagy impairments and DA neuron degeneration in an in vivo model based on known PDgenetics. The model, its well-defined pathologies, and the demonstration of a main pathogenesis pathway in the present study have set the stage and direction of emphasis for future studies.