| Blockade of PKCdelta proteolytic activation by loss of function mutants rescues mesencephalic dopaminergic neurons from methylcyclopentadienyl manganese tricarbonyl (MMT)-induced apoptotic cell death. | |
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MedLine Citation:
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PMID: 15681813 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The use of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive has raised health concerns and increased interest in understanding the neurotoxic effects of manganese. Chronic exposure to inorganic manganese causes Manganism, a neurological disorder somewhat similar to Parkinson's disease. However, the cellular mechanism by which MMT, an organic manganese compound, induces neurotoxicity in dopaminergic neuronal cells remains unclear. Therefore, we systematically investigated apoptotic cell-signaling events following exposure to 3-200 microM MMT in mesencephalic dopaminergic neuronal (N27) cells. MMT treatment resulted in a time- and dose-dependent increase in reactive oxygen species generation and cell death in N27 cells. The cell death was preceded by sequential activation of mitochondrial-dependent proapoptotic events including cytochrome c release, caspase-3 activation, and DNA fragmentation, indicating that the mitochondrial-dependent apoptotic cascade primarily triggers MMT-induced apoptotic cell death. Importantly, MMT induced proteolytic cleavage of protein kinase Cdelta (PKCdelta), resulting in persistently increased kinase activity. The proteolytic activation of PKCdelta was suppressed by treatment with 100 microM Z-VAD-FMK and 100 microM Z-DEVD-FMK, suggesting that caspase-3 mediates the proteolytic activation of PKCdelta. Pretreatment with 100 microM Z-DEVD-FMK and 5 microM rottlerin (a PKCdelta inhibitor) also significantly attenuated MMT-induced DNA fragmentation. Furthermore, overexpression of either the kinase inactive dominant negative PKCdelta(K376R) mutant or the caspase cleavage resistant PKCdelta(D327A) mutant rescued N27 cells from MMT-induced DNA fragmentation. Collectively, these results demonstrate that the mitochondrial-dependent apoptotic cascade mediates apoptosis via proteolytic activation of PKCdelta in MMT-induced dopaminergic degeneration and suggest that PKCdelta may serve as an attractive therapeutic target in Parkinson-related neurological diseases. |
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Authors:
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V Anantharam; M Kitazawa; C Latchoumycandane; A Kanthasamy; A G Kanthasamy |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Annals of the New York Academy of Sciences Volume: 1035 ISSN: 0077-8923 ISO Abbreviation: Ann. N. Y. Acad. Sci. Publication Date: 2004 Dec |
Date Detail:
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Created Date: 2005-01-31 Completed Date: 2006-07-13 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7506858 Medline TA: Ann N Y Acad Sci Country: United States |
Other Details:
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Languages: eng Pagination: 271-89 Citation Subset: IM |
Affiliation:
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Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA. akanthas@iastate.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Animals, Newborn Apoptosis / drug effects* Blotting, Western / methods Caspase 3 Caspases / metabolism Cell Count / methods DNA Fragmentation / drug effects Dopamine / metabolism* Dose-Response Relationship, Drug Enzyme Activation / drug effects Enzyme Inhibitors / pharmacology Enzyme-Linked Immunosorbent Assay / methods Flow Cytometry / methods Immunoprecipitation / methods Mesencephalon / cytology* Mutation / physiology Neurons / drug effects*, metabolism Organometallic Compounds / pharmacology* Protein Kinase C-delta / metabolism* Rats Reactive Oxygen Species / metabolism Systole Transfection / methods |
| Grant Support | |
ID/Acronym/Agency:
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ES10586/ES/NIEHS NIH HHS; NS38644/NS/NINDS NIH HHS; NS45133/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Organometallic Compounds; 0/Reactive Oxygen Species; 12108-13-3/2-methylcyclopentadienyl manganese tricarbonyl; EC 2.7.11.13/Protein Kinase C-delta; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
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