Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells

Houbo Jiang, Yong Ren, Eunice Y. Yuen, Ping Zhong, Mahboobe Ghaedi, Zhixing Hu, Gissou Azabdaftari, Kazuhiro Nakaso, Zhen Yan and Jian Feng ()
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Houbo Jiang: State University of New York at Buffalo
Yong Ren: State University of New York at Buffalo
Eunice Y. Yuen: State University of New York at Buffalo
Ping Zhong: State University of New York at Buffalo
Mahboobe Ghaedi: State University of New York at Buffalo
Zhixing Hu: State University of New York at Buffalo
Gissou Azabdaftari: Roswell Park Cancer Institute
Kazuhiro Nakaso: Tottori University
Zhen Yan: State University of New York at Buffalo
Jian Feng: State University of New York at Buffalo

Nature Communications, 2012, vol. 3, issue 1, 1-9

Abstract: Abstract Parkinson's disease (PD) is defined by the degeneration of nigral dopaminergic (DA) neurons and can be caused by monogenic mutations of genes such as parkin. The lack of phenotype in parkin knockout mice suggests that human nigral DA neurons have unique vulnerabilities. Here we generate induced pluripotent stem cells from normal subjects and PD patients with parkin mutations. We demonstrate that loss of parkin in human midbrain DA neurons greatly increases the transcription of monoamine oxidases and oxidative stress, significantly reduces DA uptake and increases spontaneous DA release. Lentiviral expression of parkin, but not its PD-linked mutant, rescues these phenotypes. The results suggest that parkin controls dopamine utilization in human midbrain DA neurons by enhancing the precision of DA neurotransmission and suppressing dopamine oxidation. Thus, the study provides novel targets and a physiologically relevant screening platform for disease-modifying therapies of PD.

Date: 2012
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DOI: 10.1038/ncomms1669

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