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
Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea.
Stem Cells. 2009 Sep;27(9):2238-46. doi: 10.1002/stem.146.
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 (Nurr1(Akt)). Overexpression of Nurr1(Akt) in NP cells yielded DA neurons in which Nurr1 protein levels were maintained for prolonged periods. The sustained Nurr1 expression endowed the Nurr1(Akt)-induced DA neurons with resistance to toxic stimuli, enhanced survival, and sustained DA phenotypes in vitro and in vivo after transplantation.
Nurr1是一种对中脑多巴胺（DA）神经元的发育和维持具有特异性的转录因子。神经前体细胞（NP）中的外源性Nurr1在体外诱导DA神经元分化，这些神经元能够逆转帕金森病啮齿动物模型中的运动功能障碍。然而，由于移植后DA细胞的细胞存活率低和表型丧失，这种治疗方法的前景尚不清楚。我们在此证明，Nurr1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Nurr1蛋白的直接Akt介导的磷酸化激活，并且可以通过消除Nurr1中的Akt靶序列（Nurr1(Akt)）来阻止。在NP细胞中过表达Nurr1(Akt)产生了DA神经元，其中Nurr1蛋白水平长时间维持。持续的Nurr1表达赋予Nurr1(Akt)诱导的DA神经元对毒性刺激的抗性、增强的存活率以及在体外和移植后体内的持续DA表型。
