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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Houbo Jiang & Yong Ren & Eunice Y. Yuen & Ping Zhong & Mahboobe Ghaedi & Zhixing Hu & Gissou Azabdaftari & Kazuhiro Nakaso & Zhen Yan & Jian Feng, 2012. "Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells," Nature Communications, Nature, vol. 3(1), pages 1-9, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1669
    DOI: 10.1038/ncomms1669
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