Mitochondrial damage by α-synuclein causes cell death in human dopaminergic neurons
Mitochondrial damage by α-synuclein causes cell death in human dopaminergic neurons
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DOI：
10.1038/s41419-019-2091-2
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发表时间：
2019-11-14
影响因子：
9
通讯作者：
Culmsee, Carsten
中科院分区：
文献类型：
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作者：
Ganjam, Goutham K.;Bolte, Kathrin;Culmsee, Carsten
帕金森氏病（PD）病理概念的演变表明，α -突触核蛋白（aSYN）通过在线粒体中的积累促进多巴胺能神经元功能障碍和死亡。然而，线粒体aSYN定位对神经元细胞线粒体结构和生物能量功能的影响尚不清楚。因此，我们研究了线粒体靶向的aSYN对分化的人多巴胺能神经元的有害影响，并与野生型（WT） aSYN过表达和相应的EGFP（增强绿色荧光蛋白）表达对照进行了比较。线粒体靶向aSYN增强线粒体活性氧（ROS）的形成，降低ATP水平，严重破坏树突神经网络的结构和功能，导致神经元死亡。透射电镜显示，WT-aSYN过表达导致嵴扭曲，线粒体碎片化，表达线粒体靶向aSYN的神经元嵴结构完全丧失，线粒体大量肿胀。此外，在分化的多巴胺能神经元中，表达WT或线粒体靶向的aSYN的线粒体生物能量分析引起了线粒体呼吸的明显损伤。在药理学化合物筛选中，我们发现泛caspase抑制剂QVD和zVAD-FMK，以及特定的caspase-1抑制剂可显著预防异步诱导的细胞死亡。此外，caspase抑制剂QVD可保护过表达aSYN的人多巴胺能神经元的线粒体功能和神经元网络活性。总的来说，我们的研究结果表明，尽管线粒体形态和功能发生了异步介导的改变，但caspase-1抑制仍有治疗效果。
Evolving concepts on Parkinson's disease (PD) pathology suggest that alpha-synuclein (aSYN) promote dopaminergic neuron dysfunction and death through accumulating in the mitochondria. However, the consequence of mitochondrial aSYN localisation on mitochondrial structure and bioenergetic functions in neuronal cells are poorly understood. Therefore, we investigated deleterious effects of mitochondria-targeted aSYN in differentiated human dopaminergic neurons in comparison with wild-type (WT) aSYN overexpression and corresponding EGFP (enhanced green fluorescent protein)-expressing controls. Mitochondria-targeted aSYN enhanced mitochondrial reactive oxygen species (ROS) formation, reduced ATP levels and showed severely disrupted structure and function of the dendritic neural network, preceding neuronal death. Transmission electron microscopy illustrated distorted cristae and many fragmented mitochondria in response to WT-aSYN overexpression, and a complete loss of cristae structure and massively swollen mitochondria in neurons expressing mitochondria-targeted aSYN. Further, the analysis of mitochondrial bioenergetics in differentiated dopaminergic neurons, expressing WT or mitochondria-targeted aSYN, elicited a pronounced impairment of mitochondrial respiration. In a pharmacological compound screening, we found that the pan-caspase inhibitors QVD and zVAD-FMK, and a specific caspase-1 inhibitor significantly prevented aSYN-induced cell death. In addition, the caspase inhibitor QVD preserved mitochondrial function and neuronal network activity in the human dopaminergic neurons overexpressing aSYN. Overall, our findings indicated therapeutic effects by caspase-1 inhibition despite aSYN-mediated alterations in mitochondrial morphology and function.