Parkin absence accelerates microtubule aging in dopaminergic neurons
Parkin absence accelerates microtubule aging in dopaminergic neurons
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DOI：
10.1016/j.neurobiolaging.2017.09.010
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发表时间：
2018-01-01
影响因子：
4.2
通讯作者：
Cappelletti, Graziella
中科院分区：
文献类型：
--
作者：
Cartelli, Daniele;Amadeo, Alida;Cappelletti, Graziella
由parkin基因（PARK2）突变引起的功能丧失导致早发性家族性帕金森病。近年来，研究表明parkin具有调节线粒体稳态和微管稳定性的作用。在PARK2基因敲除小鼠衰老过程中观察这些系统，我们发现parkin的缺失诱导了分别位于黑质和纹状体的多巴胺能神经元细胞体和纤维中MT系统的加速（过度）乙酰化。有趣的是，在PARK2基因敲除小鼠中，MT稳定性的变化先于线粒体转运的改变。此外，细胞内实验证实，parkin的损失影响线粒体的流动性，并表明这种缺陷取决于MT系统，因为它是由紫杉醇，一个众所周知的MT靶向剂拯救。此外，在PC12神经元细胞和患者的诱导多能干细胞衍生的中脑神经元中，我们观察到parkin缺陷导致稳定MT的片段化。因此，我们认为，parkin作为一个调节MT系统在神经元老化，我们赞同的假设，MT功能障碍可能是至关重要的帕金森病的发病机制。(C)2017爱思唯尔公司All rights reserved.
Loss-of-function caused by mutations in the parkin gene (PARK2) lead to early-onset familial Parkinson's disease. Recently, mechanistic studies proved the ability of parkin in regulating mitochondria homeostasis and microtubule (MT) stability. Looking at these systems during aging of PARK2 knockout mice, we found that loss of parkin induced an accelerated (over)acetylation of MT system both in dopaminergic neuron cell bodies and fibers, localized in the substantia nigra and corpus striatum, respectively. Interestingly, in PARK2 knockout mice, changes of MT stability preceded the alteration of mitochondria transport. Moreover, in-cell experiments confirmed that loss of parkin affects mitochondria mobility and showed that this defect depends on MT system as it is rescued by paclitaxel, a well-known MT-targeted agent. Furthermore, both in PC12 neuronal cells and in patients' induced pluripotent stem cell-derived midbrain neurons, we observed that parkin deficiencies cause the fragmentation of stable MTs. Therefore, we suggest that parkin acts as a regulator of MT system during neuronal aging, and we endorse the hypothesis that MT dysfunction may be crucial in the pathogenesis of Parkinson's disease. (C) 2017 Elsevier Inc. All rights reserved.