title: Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis.
abstract: Parkinson's disease (PD) is characterized by the selective degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc). A combination of genetic and environmental factors contributes to such a specific loss. Among the five PD-linked genes identified so far, parkin, a protein-ubiquitin E3 ligase, appears to be the most prevalent genetic factor in PD. Although a variety of substrates have been identified for parkin, none of them is selectively expressed in nigral DA neurons. It remains unclear how accumulation of these substrates in the absence of functional parkin may cause the selective death of DA neurons in SNpc. Here, we show that overexpression of parkin protected human DA neuroblastoma cell line (SH-SY5Y) against apoptosis induced by DA or 6-OHDA, but not by H(2)O(2) or rotenone. Parkin significantly attenuated dopamine-induced activation of c-Jun N-terminal kinase (JNK) and caspase-3. It also decreased the level of reactive oxygen species (ROS) and protein carbonyls in the cell. Inhibiting DA uptake through dopamine transporter or treating the cell with antioxidants significantly reduced oxidative stress and dopamine toxicity. Furthermore, PD-linked mutations of parkin significantly abrogated the protective effect of wild-type parkin, as well as its ability to suppress ROS and protein carbonylation. These results suggest that parkin protects against dopamine toxicity by decreasing oxidative stress and ensuing activation of apoptotic programs such as the JNK/caspase pathway. This protective function of parkin, which is greatly attenuated by its PD-linked mutations, may be uniquely important for the survival of DA neurons, as they are constantly threatened by oxyradicals produced during dopamine oxidation.
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, 14214, USA.
authors.forename: Houbo
authors.initials: H
authors.lastname: Jiang
authors.forename: Yong
authors.initials: Y
authors.lastname: Ren
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhao
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004298:Dopamine / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D012402:Rotenone; D006861:Hydrogen Peroxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D004298:Dopamine