Berthet Amandine, Margolis Elyssa B, Zhang Jue, Hsieh Ivy, Zhang Jiasheng, Hnasko Thomas S, Ahmad Jawad, Edwards Robert H, Sesaki Hiromi, Huang Eric J, Nakamura Ken
Gladstone Institute of Neurological Disease, San Francisco, California 94158.
Department of Neurology and.
J Neurosci. 2014 Oct 22;34(43):14304-17. doi: 10.1523/JNEUROSCI.0930-14.2014.
Disruptions in mitochondrial dynamics may contribute to the selective degeneration of dopamine (DA) neurons in Parkinson's disease (PD). However, little is known about the normal functions of mitochondrial dynamics in these neurons, especially in axons where degeneration begins, and this makes it difficult to understand the disease process. To study one aspect of mitochondrial dynamics-mitochondrial fission-in mouse DA neurons, we deleted the central fission protein dynamin-related protein 1 (Drp1). Drp1 loss rapidly eliminates the DA terminals in the caudate-putamen and causes cell bodies in the midbrain to degenerate and lose α-synuclein. Without Drp1, mitochondrial mass dramatically decreases, especially in axons, where the mitochondrial movement becomes uncoordinated. However, in the ventral tegmental area (VTA), a subset of midbrain DA neurons characterized by small hyperpolarization-activated cation currents (Ih) is spared, despite near complete loss of their axonal mitochondria. Drp1 is thus critical for targeting mitochondria to the nerve terminal, and a disruption in mitochondrial fission can contribute to the preferential death of nigrostriatal DA neurons.
线粒体动力学的破坏可能导致帕金森病（PD）中多巴胺（DA）神经元的选择性退化。然而，对于这些神经元中线粒体动力学的正常功能，尤其是在退化起始的轴突中的功能，我们知之甚少，这使得理解疾病过程变得困难。为了研究小鼠DA神经元中线粒体动力学的一个方面——线粒体分裂，我们删除了中心分裂蛋白动力相关蛋白1（Drp1）。Drp1缺失迅速消除了尾状核-壳核中的DA终末，并导致中脑的细胞体退化并失去α-突触核蛋白。没有Drp1，线粒体质量显著下降，尤其是在轴突中，线粒体运动变得不协调。然而，在腹侧被盖区（VTA），以小的超极化激活阳离子电流（Ih）为特征的一部分中脑DA神经元得以幸免，尽管其轴突线粒体几乎完全丧失。因此，Drp1对于将线粒体靶向神经终末至关重要，线粒体分裂的破坏可能导致黑质纹状体DA神经元的选择性死亡。
