α-Synuclein Regulates Iron Homeostasis via Preventing Parkin-Mediated DMT1 Ubiquitylation in Parkinson's Disease Models
α-Synuclein Regulates Iron Homeostasis via Preventing Parkin-Mediated DMT1 Ubiquitylation in Parkinson's Disease Models
复制标题
α-突触核蛋白通过防止帕金森病模型中 Parkin 介导的 DMT1 泛素化来调节铁稳态
DOI：
10.1021/acschemneuro.0c00196
复制
发表时间：
2020-06-03
影响因子：
5
通讯作者：
Jiang, Hong
中科院分区：
文献类型：
--
作者：
Bi, Mingxia;Du, Xixun;Jiang, Hong
铁代谢失衡在帕金森病（PD）的神经退行性变中起着重要作用，铁稳态的维持需要铁转运蛋白的严密调控。α-突触核蛋白（alpha-Syn）是一种铁还原酶和铁结合蛋白，被认为与铁代谢有关，但关于alpha-Syn如何影响PD患者体内铁平衡的研究却知之甚少。我们以前的研究结果，二价金属转运蛋白1（DMT 1）的上调占黑质铁的积累在PD提出的问题，是否α-Syn干扰铁稳态通过调节DMT 1的表达。使用α-Syn过表达的SH-SY 5 Y细胞和突变的人A53 T α-Syn转基因小鼠，我们发现α-Syn可以上调DMT 1蛋白水平，随后增加亚铁内流，随后加重氧化应激损伤。机制研究表明，α-Syn诱导的p38丝裂原活化蛋白激酶（MAPK）活化使parkin在Ser 131处磷酸化，从而使parkin的E3泛素连接酶活性失活，并进一步降低DMT 1泛素化水平。我们的研究结果表明，alpha-Syn通过调节DMT 1蛋白的稳定性和改变细胞铁摄取来影响脑铁稳态，这可能为alpha-Syn参与铁代谢功能障碍提供直接证据，并为PD相关的黑质铁沉积提供新的见解。
Iron metabolism imbalance plays a key role in the neurodegeneration of Parkinson's disease (PD), thus iron homeostasis should be tightly controlled by iron transporters. alpha-Synuclein (alpha-Syn) serves as a ferrireductase and iron-binding protein, which is supposed to be linked with iron metabolism, but little is known about how alpha-Syn affects iron homeostasis in PD. Our previous findings that up-regulation of divalent metal transporter 1 (DMT1) accounted for the nigral iron accumulation in PD raised the question whether alpha-Syn disturbed iron homeostasis by modulating DMT1 expression. Using alpha-Syn overexpressed SH-SY5Y cells and mutant human A53T alpha-Syn transgenic mice, we found that alpha-Syn could upregulate DMT1 protein levels, followed by enhanced ferrous iron influx and subsequent aggravated oxidative stress injury. Mechanistic studies identified that alpha-Syn-induced p38 mitogen-activated protein kinase (MAPK) activation phosphorylated parkin at Ser131, which inactivated parkin's E3 ubiquitin ligase activity and further reduced DMT1 ubiquitylation level. Our findings revealed that alpha-Syn affected brain iron homeostasis through modulating DMT1 protein stability and altering cellular iron uptake, which might provide direct evidence for the involvement of alpha-Syn in iron metabolism dysfunction and provide insight into PD-associated nigral iron deposition.