Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
J Neurosci. 2011 May 11;31(19):7212-21. doi: 10.1523/JNEUROSCI.0711-11.2011.
Impaired axonal transport may play a key role in Parkinson's disease. To test this notion, a microchamber system was adapted to segregate axons from cell bodies using green fluorescent protein-labeled mouse dopamine (DA) neurons. Transport was examined in axons challenged with the DA neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+). MPP+ rapidly reduced overall mitochondrial motility in DA axons; among motile mitochondria, anterograde transport was slower yet retrograde transport was increased. Transport effects were specific for DA mitochondria, which were smaller and transported more slowly than their non-DA counterparts. MPP+ did not affect synaptophysin-tagged vesicles or any other measureable moving particle. Toxin effects on DA mitochondria were not dependent upon ATP, calcium, free radical species, JNK, or caspase3/PKC pathways but were completely blocked by the thiol-anti-oxidant N-acetyl-cysteine or membrane-permeable glutathione. Since these drugs also rescued processes from degeneration, these findings emphasize the need to develop therapeutics aimed at axons as well as cell bodies to preserve "normal" circuitry and function as long as possible.
轴突运输障碍可能在帕金森病中起关键作用。为了验证这一观点，我们采用微室系统将绿色荧光蛋白标记的小鼠多巴胺（DA）神经元从细胞体中分离出来，以研究轴突。使用多巴胺神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPP+）对轴突进行了检测。MPP+ 可迅速降低 DA 轴突中线粒体的整体迁移率；在可迁移的线粒体中，正向运输变慢，但逆向运输增加。这些运输效应是 DA 线粒体特有的，DA 线粒体比非 DA 线粒体更小，迁移速度更慢。MPP+ 不影响突触小体标记的囊泡或任何其他可测量的运动颗粒。DA 线粒体对毒素的反应不依赖于 ATP、钙、自由基种类、JNK 或 caspase3/PKC 途径，但可被硫醇抗氧化剂 N-乙酰半胱氨酸或膜通透型谷胱甘肽完全阻断。由于这些药物还能挽救退变过程，这些发现强调了有必要开发针对轴突以及细胞体的治疗方法，以尽可能长时间地保护“正常”的电路和功能。
