Parkin protects against tyrosinase-mediated dopamine neurotoxicity by suppressing stress-activated protein kinase pathways.
Parkinson's disease (PD) motor symptoms are caused by degeneration of nigrostriatal dopaminergic (DAergic) neurons. The most common causes of hereditary PD are mutations in the PARKIN gene. The ubiquitin ligase parkin has been shown to mediate neuroprotection in cell culture and in vivo, but the molecular mechanisms are not well understood. We investigated the effects of parkin in a human SH-SY5Y neuroblastoma cell culture model of PD, in which transcriptional induction of the enzyme tyrosinase causes a neurotoxic overproduction of cellular DA and its oxidative metabolites. Tyrosinase induction caused formation of reactive oxygen species in the cytosol and mitochondria, and neurotoxicity via activation of apoptotic stress-activated protein kinases and caspase 3. Stable transfection of wild-type parkin suppressed tyrosinase-induced apoptosis, and PD-associated mutations abolished the neuroprotective effect of parkin. Expression of wild-type parkin did not affect reactive oxygen species production, but attenuated the tyrosinase-induced activation of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase as well as their cognate mitogen-activated protein kinase kinases. PD-associated mutations differentially affected the anti-apoptotic signaling of parkin. Thus, parkin contributes to DAergic neuroprotection by suppression of apoptotic stress-activated protein kinase pathways.
Hasegawa
Takafumi
T
Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University Clinics Tübingen, Tübingen, Germany.
Treis
Angela
A
Patenge
Nadja
N
Fiesel
Fabienne C
FC
Springer
Wolfdieter
W
Kahle
Philipp J
PJ
D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D004298:Dopamine / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D014442:Monophenol Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine