Generation of dopamine neurons with improved cell survival and phenotype maintenance using a degradation-resistant nurr1 mutant.
Generation of dopamine neurons with improved cell survival and phenotype maintenance using a degradation-resistant nurr1 mutant.
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DOI：
10.1002/stem.146
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发表时间：
2009-09
期刊：
影响因子：
5.2
通讯作者：
Lee, Sang-Hun
中科院分区：
文献类型：
--
作者：
Jo, A-Young;Kim, Mi-Young;Lee, Hyun-Seob;Rhee, Yong-Hee;Lee, Jeong-Eun;Baek, Kwang-Hyun;Park, Chang-Hwan;Koh, Hyun-Chul;Shin, Incheol;Lee, Yong-Sung;Lee, Sang-Hun
Nurr 1是中脑多巴胺（DA）神经元发育和维持的特异性转录因子。神经前体（NP）细胞中的外源性Nurr 1在体外诱导能够逆转帕金森病啮齿动物模型中运动功能障碍的DA神经元的分化。然而，由于移植后DA细胞的细胞存活率差和表型丢失，这种治疗方法的前景尚不清楚。我们在此证明Nurr 1蛋白在分化的NP细胞中经历泛素-蛋白酶体系统介导的降解。降解过程由Nurr 1蛋白的直接Akt介导的磷酸化激活，并且可以通过废除Nurr 1中的Akt靶序列（Nurr 1Akt）来防止。Nurr 1Akt在NP细胞中的过表达产生了DA神经元，其中Nurr 1蛋白水平维持了很长一段时间。持续的Nurr 1表达赋予了Nurr 1Akt诱导的DA神经元对毒性刺激的抵抗力，增强了存活率，并在移植后的体外和体内维持了DA表型。
Nurr1 is a transcription factor specific for the development and maintenance of the midbrain dopamine (DA) neurons. Exogenous Nurr1 in neural precursor (NP) cells induces the differentiation of DA neurons in vitro that are capable of reversing motor dysfunctions in a rodent model for Parkinson disease. The promise of this therapeutic approach, however, is unclear due to poor cell survival and phenotype loss of DA cells after transplantation. We herein demonstrate that Nurr1 proteins undergo ubiquitin-proteasome-system-mediated degradation in differentiating NP cells. The degradation process is activated by a direct Akt-mediated phosphorylation of Nurr1 proteins and can be prevented by abolishing the Akt-target sequence in Nurr1 (Nurr1Akt). Overexpression of Nurr1Akt in NP cells yielded DA neurons in which Nurr1 protein levels were maintained for prolonged periods. The sustained Nurr1 expression endowed the Nurr1Akt-induced DA neurons with resistance to toxic stimuli, enhanced survival, and sustained DA phenotypes in vitro and in vivo after transplantation.
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通讯作者：
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影响因子：
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