title: Inhibition of Mitochondrial Clearance and Cu/Zn-SOD Activity Enhance 6-Hydroxydopamine-Induced Neuronal Apoptosis.
abstract: Parkinson's disease (PD) is a common movement disorder among neurodegenerative diseases, involving neuronal cell death in the substantia nigra of the midbrain. Although mechanisms of cell death in PD have been studied, the exact molecular pathogenesis is still unclear. Here, we explore the relationship between two types of cell death, autophagy and apoptosis, which have been studied separately in parkinsonian mimetic model of 6-hydroxydopamine (6-OHDA). 6-OHDA induced autophagy firstly and then later inhibition of autophagy flux occurred with apoptosis. The apoptosis was prevented by treatment of pan-caspase inhibitor, zVAD-fmk (benzyloxycarbonyl-VAD-fluoromethylketone (zVAD)), or early phase inhibitor of autophagy, 3-methyladenine (3-MA), indicating that autophagic induction was followed by the apoptosis. Interestingly, late step inhibitor of autophagy, bafilomycin A1 (BafA), aggravated 6-OHDA-induced apoptosis. This was associated with mitochondrial abnormality such as the inhibition of damaged mitochondrial clearance and aberrant increase of extracellular oxygen consumption. Furthermore, treatment of BafA did not inhibit 6-OHDA-mediated superoxide formation but strongly reduced the hydrogen peroxide production to below basal levels, indicating failure from superoxide to hydrogen peroxide. These results were accompanied by a lowered expression and activity of copper/zinc superoxide dismutase (Cu/Zn-SOD) but not of manganese SOD (MnSOD) and catalase. Thus, the present study suggests that crosstalk among apoptosis, autophagy, and oxidative stress is a causative factor of 6-OHDA-induced neuronal death and provides a mechanistic understanding of PD pathogenesis.
authors: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-Do, 200-702, South Korea.
authors: Sua
authors: S
authors: In
authors: Department of Pharmacology, College of Medicine, Hallym University, Chuncheon, Gangwon-Do, 200-702, South Korea.
authors: Chang-Won
authors: CW
authors: Hong
authors: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-Do, 200-702, South Korea.
authors: Boyoung
authors: B
authors: Choi
authors: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-Do, 200-702, South Korea.
authors: Bong-Geum
authors: BG
authors: Jang
authors: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-Do, 200-702, South Korea. zolim@hallym.ac.kr.
authors: Min-Ju
authors: MJ
authors: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016627:Oxidopamine; D013482:Superoxide Dismutase
keywords: 6-Hydroxydopamine; Apoptosis; Autophagy; Parkinson’s disease; Reactive oxygen species; Superoxide dismutase
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