Generation of Dopamine Neurons with Improved Cell Survival and Phenotype Maintenance Using a Degradation-Resistant Nurr1 Mutant

被引：27

作者：

Jo, A-Young ^{[1
,2
,3
]}

Kim, Mi-Young ^{[1
,2
,3
]}

Lee, Hyun-Seob ^{[1
,2
,3
]}

Rhee, Yong-Hee ^{[1
,2
,3
]}

Lee, Jeong-Eun ^{[2
,3
,4
]}

Baek, Kwang-Hyun ^{[5
]}

Park, Chang-Hwan ^{[2
,3
,6
]}

Koh, Hyun-Chul ^{[2
,3
,4
]}

Shin, Incheol ^{[7
]}

Lee, Yong-Sung ^{[1
,2
,3
]}

Lee, Sang-Hun ^{[1
,2
,3
]}

机构：

[1] Hanyang Univ, Dept Biochem & Mol Biol, Coll Med, Seoul 133791, South Korea

[2] Hanyang Univ, Inst Mental Hlth, Coll Med, Seoul 133791, South Korea

[3] Hanyang Univ, Cell Therapy Res Ctr, Coll Med, Seoul 133791, South Korea

[4] Hanyang Univ, Dept Pharmacol, Coll Med, Seoul 133791, South Korea

[5] CHA Univ, CHA Gen Hosp, Dept Biomed Sci, Lab Mol Signal Transduct, Seoul, South Korea

[6] Hanyang Univ, Dept Microbiol, Coll Med, Seoul 133791, South Korea

[7] Hanyang Univ, Dept Life Sci, Coll Nat Sci, Seoul 133791, South Korea

来源：

STEM CELLS | 2009年 / 27卷 / 09期

关键词：

Nurr1; Dopamine neuron; Ubiquitin-proteasome-system; Cell survival; Midbrain; Akts; TYROSINE-HYDROXYLASE EXPRESSION; NEURAL PRECURSOR CELLS; IN-VITRO; PARKINSONS-DISEASE; STEM-CELLS; DIFFERENTIATION; PHOSPHORYLATION; MICE; AKT; ACTIVATION;

D O I：

10.1002/stem.146

中图分类号：

Q813 [细胞工程];

学科分类号：

100113 [医学细胞生物学];

摘要：

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. STEM CELLS 2009; 27: 2238-2246

引用

页码：2238 / 2246

页数：9

共 35 条

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