07 February 2012
Jiang H, Ren Y, Yuen EY, Zhong P, Ghaedi M, Hu Z, Azabdaftari G, Nakaso K, Yan Z, Feng J
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.
