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

Overview

Journal Stem Cells

Publisher Oxford University Press

Specialties Cell Biology
Reproductive Medicine

Date 2009 Jun 13

PMID 19522012

Citations 20

Authors

A-Young Jo

Mi-Young Kim

Hyun-Seob Lee

Yong-Hee Rhee

Jeong-Eun Lee

Kwang-Hyun Baek

Chang-Hwan Park

Hyun-Chul Koh

Incheol Shin

Yong-Sung Lee

Sang-Hun Lee

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Mechanisms of NURR1 Regulation: Consequences for Its Biological Activity and Involvement in Pathology.

Garcia-Yague A, Cuadrado A Int J Mol Sci. 2023; 24(15).

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α-Synuclein Induces the GSK-3-Mediated Phosphorylation and Degradation of NURR1 and Loss of Dopaminergic Hallmarks.

Garcia-Yague A, Lastres-Becker I, Stefanis L, Vassilatis D, Cuadrado A Mol Neurobiol. 2021; 58(12):6697-6711.

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