Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson’s disease
Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson’s disease
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DOI：
10.1093/hmg/ddx201
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发表时间：
2016-11
影响因子：
3.5
通讯作者：
Kahori Shiba-Fukushima;K. Ishikawa;T. Inoshita;N. Izawa;M. Takanashi;Shigeto Sato;O. Onodera;W. Akamatsu;H. Okano;Y. Imai;N. Hattori
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文献类型：
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作者：
Kahori Shiba-Fukushima;K. Ishikawa;T. Inoshita;N. Izawa;M. Takanashi;Shigeto Sato;O. Onodera;W. Akamatsu;H. Okano;Y. Imai;N. Hattori
泛素（Ub）激酶PINK 1和E3 Ub连接酶帕金，两个与帕金森病（PD）相关的基因产物，参与线粒体质量控制。PINK 1以线粒体膜电位（Δ μ m）依赖性方式激活线粒体polyUb的磷酸化，促进线粒体易位和伴随的帕金酶激活，导致磷酸化polyUb标记的线粒体通过线粒体自噬清除。因此，Ub磷酸化是PINK 1-Parkin介导的线粒体自噬中的关键事件。在这里，我们使用果蝇PD模型，人脑组织和来自含有Parkin或PINK 1突变的诱导多能干细胞（iPSC）的多巴胺能神经元以及正常对照，研究了磷酸化Ub信号在PD发病机制中的作用。我们报道了磷酸化Ub信号在人类和果蝇之间是高度保守的，并且磷酸化Ub信号和轴突线粒体的重新定位在含有Parkin或PINK 1突变的人类多巴胺能神经元中确实受到损害。此外，与酪氨酸羟化酶阴性神经元相比，酪氨酸羟化酶阳性神经元中磷酸化Ub信号是突出的，这表明PINK 1-Parkin信号对于多巴胺能神经元更需要。这些结果揭示了多巴胺能神经元对线粒体应激的特殊脆弱性。
The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (ΔΨm)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls. We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon ΔΨm reduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.