Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons.
Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons.
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Parkin突变降低了IPSC衍生的人类神经元中神经元过程的复杂性。
DOI：
10.1002/stem.1854
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发表时间：
2015-01
期刊：
影响因子：
5.2
通讯作者：
Feng, Jian
中科院分区：
文献类型：
--
作者：
Ren, Yong;Jiang, Houbo;Hu, Zhixing;Fan, Kevin;Wang, Jun;Janoschka, Stephen;Wang, Xiaomin;Ge, Shaoyu;Feng, Jian
帕金森病(PD)是以黑质多巴胺(DA)能神经元和非DA能神经元变性为特征的疾病。Parkin是一种与微管紧密结合的E3泛素连接酶，Parkin的突变是隐性遗传性帕金森病的最常见原因。Parkin基因敲除小鼠缺乏强健的PD表型，这表明人类神经元对Parkin突变具有独特的脆弱性。在这里，我们表明，在帕金森突变的帕金森病患者的诱导多能干细胞来源的TH+或TH−神经元中，通过轴突总长度、终末数量、分支点数量和SHOL分析来衡量神经元过程的复杂性大大降低。与此一致的是，IPSC来源的神经元中的parkin突变显著降低了微管的稳定性。Parkin的过度表达，而不是其PD相关突变体或GFP的过度表达，恢复了神经元过程的复杂性和微管的稳定性。与此一致的是，微管解聚剂秋水仙碱通过减少对照神经元的轴突长度和复杂性来模拟parkin突变的影响，而微管稳定剂紫杉醇通过增强parkin缺陷神经元的形态来模拟parkin过度表达的影响。结果表明，parkin通过稳定微管来维持人类神经元的形态复杂性。
Parkinson’s disease (PD) is characterized by the degeneration of nigral dopaminergic (DA) neurons and non-DA neurons in many parts of the brain. Mutations of parkin, an E3 ubiquitin ligase that strongly binds to microtubules, are the most frequent cause of recessively inherited Parkinson’s disease. The lack of robust PD phenotype in parkin knockout mice suggests a unique vulnerability of human neurons to parkin mutations. Here, we show that the complexity of neuronal processes as measured by total neurite length, number of terminals, number of branch points and Sholl analysis, was greatly reduced in induced pluripotent stem cell (iPSC)-derived TH+ or TH− neurons from PD patients with parkin mutations. Consistent with these, microtubule stability was significantly decreased by parkin mutations in iPSC-derived neurons. Overexpression of parkin, but not its PD-linked mutant nor GFP, restored the complexity of neuronal processes and the stability of microtubules. Consistent with these, the microtubule-depolymerizing agent colchicine mimicked the effect of parkin mutations by decreasing neurite length and complexity in control neurons while the microtubule-stabilizing drug taxol mimicked the effect of parkin overexpression by enhancing the morphology of parkin-deficient neurons. The results suggest that parkin maintains the morphological complexity of human neurons by stabilizing microtubules.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
3.9
作者：
Nuytemans, Karen;Theuns, Jessie;Cruts, Marc;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
DOI：
10.1083/jcb.200809125
发表时间：
2008-12-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Feng, J
影响因子：
5.3
作者：
Matsuda, Wakoto;Furuta, Takahiro;Kaneko, Takeshi
通讯作者：
Kaneko, Takeshi