CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice
CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice
复制标题
DOI：
10.1083/jcb.201709028
复制
发表时间：
2019-01-01
影响因子：
7.8
通讯作者：
La Spada, Albert R.
中科院分区：
文献类型：
--
作者：
Gilmore-Hall, Stephen;Kuo, Jennifer;La Spada, Albert R.
神经变性中一个令人困惑的问题是为什么不同的神经元会变性。浦肯野细胞变性（pcd）小鼠表现出小脑浦肯野细胞变性的显着表型。微管蛋白 CCP1/Nna1 去谷氨酰化的丧失导致 PCD 神经变性，但其机制尚不清楚。在这项研究中，我们调节了果蝇功能丧失模型中裂变和融合基因的剂量，发现线粒体碎片和疾病表型可以通过减少 Drp1 来挽救。我们在 CCP1 缺失细胞和 PCD 小鼠的神经元中观察到线粒体断裂，并记录了缺乏 CCP1 的细胞中线粒体融合减少。我们检查了微管蛋白高谷氨酰化对 PCD 神经元中微管介导的线粒体运动的影响，并注意到逆行轴突运输显着减少。线粒体应激促进了 CCP1 的 Parkin 依赖性更新，并且 CCP1 和 Parkin 发生物理相互作用。我们的结果表明，CCP1 通过微管蛋白的去谷氨酰化来调节线粒体运动，而 CCP1 介导的线粒体融合的丧失是 PCD 小鼠浦肯野神经元极其脆弱的原因。
A perplexing question in neurodegeneration is why different neurons degenerate. The Purkinje cell degeneration (pcd) mouse displays a dramatic phenotype of degeneration of cerebellar Purkinje cells. Loss of CCP1/Nna1 deglutamylation of tubulin accounts for pcd neurodegeneration, but the mechanism is unknown. In this study, we modulated the dosage of fission and fusion genes in a Drosophila melanogaster loss-of-function model and found that mitochondrial fragmentation and disease phenotypes were rescued by reduced Drp1. We observed mitochondrial fragmentation in CCP1 null cells and in neurons from pcd mice, and we documented reduced mitochondrial fusion in cells lacking CCP1. We examined the effect of tubulin hyperglutamylation on microtubule-mediated mitochondrial motility in pcd neurons and noted markedly reduced retrograde axonal transport. Mitochondrial stress promoted Parkin-dependent turnover of CCP1, and CCP1 and Parkin physically interacted. Our results indicate that CCP1 regulates mitochondrial motility through deglutamylation of tubulin and that loss of CCP1-mediated mitochondrial fusion accounts for the exquisite vulnerability of Purkinje neurons in pcd mice.