Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells.
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.
Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York 14214, USA.
Houbo
H
Jiang
Yong
Y
Ren
Eunice Y
EY
Yuen
Ping
P
Zhong
Mahboobe
M
Ghaedi
Zhixing
Z
Hu
Gissou
G
Azabdaftari
Kazuhiro
K
Nakaso
Zhen
Z
Yan
Jian
J
Feng
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000196:embryology*; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008995:Monoamine Oxidase / Q000096:biosynthesis; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D010300:Parkinson Disease / Q000378:metabolism*; D010641:Phenotype; D012867:Skin / Q000378:metabolism; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D008995:Monoamine Oxidase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D010100:Oxygen; D004298:Dopamine