Centre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada.
Neurotox Res. 2012 Nov;22(4):355-64. doi: 10.1007/s12640-012-9325-8. Epub 2012 Apr 20.
Delineation of how cell death mechanisms associated with Parkinson's disease (PD) interact and whether they converge would help identify targets for neuroprotective therapies. The purpose of this study was to use a cellular model to address these issues. Catecholaminergic SH-SY5Y neuroblastoma cells were exposed to a range of compounds (dopamine, rotenone, 5,8-dihydroxy-1,4-naphtho-107 quinone [naphthazarin], and Z-Ile-Glu(OBut)-Ala-Leu-al [PSI]) that are neurotoxic when applied to these cells for extended periods of times at specific concentrations. At the concentrations used, these compounds cause cellular stress via mechanisms that mimic those associated with causing neurodegeneration in PD, namely oxidative stress (dopamine), mitochondrial dysfunction (rotenone), lysosomal dysfunction (naphthazarin), and proteasomal dysfunction (PSI). The compounds were applied to the SH-SY5Y cells either alone or in pairs. When applied separately, the compounds produced a significant decrease in cell viability confirming that oxidative stress, mitochondrial, proteosomal, or lysosomal dysfunction can individually result in catecholaminergic cell death. When the compounds were applied in pairs, some of the combinations produced synergistic effects. Analysis of these interactions indicates that proteasomal, lysosomal, and mitochondrial dysfunction is exacerbated by dopamine-induced oxidative stress. Furthermore, inhibition of the proteasome or lysosome or increasing oxidative stress has a synergistic effect on cell viability when combined with mitochondrial dysfunction, suggesting that all cell death mechanisms impair mitochondrial function. Finally, we show that there are reciprocal relationships between oxidative stress, proteasomal dysfunction, and mitochondrial dysfunction, whereas lysosome dysfunction appears to mediate cell death via an independent pathway. Given the highly interactive nature of the various cell death mechanisms linked with PD, we predict that effective neuroprotective strategies should target multiple sites in these pathways, for example oxidative stress and mitochondria.
阐明与帕金森病（PD）相关的细胞死亡机制如何相互作用以及它们是否会聚将有助于确定神经保护治疗的靶点。本研究的目的是使用细胞模型来解决这些问题。儿茶酚胺能 SH-SY5Y 神经母细胞瘤细胞暴露于一系列化合物（多巴胺、鱼藤酮、5,8-二羟基-1,4-萘醌[萘唑嗪]和 Z-Ile-Glu（OBut）-Ala-Leu-al[PSI]），这些化合物在特定浓度下长时间应用于这些细胞时会产生神经毒性。在使用的浓度下，这些化合物通过模拟导致 PD 中神经退行性变的机制引起细胞应激，即氧化应激（多巴胺）、线粒体功能障碍（鱼藤酮）、溶酶体功能障碍（萘唑嗪）和蛋白酶体功能障碍（PSI）。这些化合物单独或成对应用于 SH-SY5Y 细胞。当单独应用时，这些化合物导致细胞活力显着下降，证实氧化应激、线粒体、蛋白酶体或溶酶体功能障碍均可单独导致儿茶酚胺能细胞死亡。当这些化合物成对应用时，一些组合产生协同作用。对这些相互作用的分析表明，蛋白酶体、溶酶体和线粒体功能障碍被多巴胺诱导的氧化应激加剧。此外，当与线粒体功能障碍结合时，蛋白酶体或溶酶体的抑制或氧化应激的增加对细胞活力具有协同作用，这表明所有细胞死亡机制都会损害线粒体功能。最后，我们表明氧化应激、蛋白酶体功能障碍和线粒体功能障碍之间存在相互关系，而溶酶体功能障碍似乎通过独立途径介导细胞死亡。鉴于与 PD 相关的各种细胞死亡机制之间的高度交互性质，我们预测有效的神经保护策略应该针对这些途径中的多个位点，例如氧化应激和线粒体。
