Blockade of PKCδ Proteolytic Activation by Loss of Function Mutants Rescues Mesencephalic Dopaminergic Neurons from Methylcyclopentadienyl Manganese Tricarbonyl (MMT)‐Induced Apoptotic Cell Death
Identifieur interne : 001667 ( Main/Exploration ); précédent : 001666; suivant : 001668Blockade of PKCδ Proteolytic Activation by Loss of Function Mutants Rescues Mesencephalic Dopaminergic Neurons from Methylcyclopentadienyl Manganese Tricarbonyl (MMT)‐Induced Apoptotic Cell Death
Auteurs : V. Anantharam [États-Unis] ; M. Kitazawa [États-Unis] ; C. Latchoumycandane [États-Unis] ; A. Kanthasamy [États-Unis] ; A G Kanthasamy [États-Unis]Source :
- Annals of the New York Academy of SciencesProtective Strategies for Neurodegenerative Diseases [ 0077-8923 ] ; 2004-12.
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Abstract
Abstract: 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 μM 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 Cδ (PKCδ), resulting in persistently increased kinase activity. The proteolytic activation of PKCδ was suppressed by treatment with 100 μM Z‐VAD‐FMK and 100 μM Z‐DEVD‐FMK, suggesting that caspase‐3 mediates the proteolytic activation of PKCδ. Pretreatment with 100 μM Z‐DEVD‐FMK and 5 μM rottlerin (a PKCδ inhibitor) also significantly attenuated MMT‐induced DNA fragmentation. Furthermore, overexpression of either the kinase inactive dominant negative PKCδK376R mutant or the caspase cleavage resistant PKCδD327A 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 PKCδ in MMT‐induced dopaminergic degeneration and suggest that PKCδ may serve as an attractive therapeutic target in Parkinson‐related neurological diseases.
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DOI: 10.1196/annals.1332.017
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Kanthasamy</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011–1250</wicri:regionArea><wicri:noRegion>Iowa 50011–1250</wicri:noRegion></affiliation></author><author><name sortKey="Kanthasamy, A G" sort="Kanthasamy, A G" uniqKey="Kanthasamy A" first="A G" last="Kanthasamy">A G Kanthasamy</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011–1250</wicri:regionArea><wicri:noRegion>Iowa 50011–1250</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of the New York Academy of SciencesProtective Strategies for Neurodegenerative Diseases</title><idno type="ISSN">0077-8923</idno><idno type="eISSN">1749-6632</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2004-12">2004-12</date><biblScope unit="volume">1035</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="271">271</biblScope><biblScope unit="page" to="289">289</biblScope></imprint><idno type="ISSN">0077-8923</idno></series><idno type="istex">6251442B9FBB0FC3E5D54CCB5F286EE8960585F5</idno><idno type="DOI">10.1196/annals.1332.017</idno><idno type="ArticleID">NYAS271</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0077-8923</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>PKCdelta</term><term>Parkinson's disease (PD)</term><term>caspases</term><term>kinase</term><term>manganese</term><term>neuroprotection</term><term>neurotoxicity</term><term>oxidative stress</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: 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 μM 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 Cδ (PKCδ), resulting in persistently increased kinase activity. The proteolytic activation of PKCδ was suppressed by treatment with 100 μM Z‐VAD‐FMK and 100 μM Z‐DEVD‐FMK, suggesting that caspase‐3 mediates the proteolytic activation of PKCδ. Pretreatment with 100 μM Z‐DEVD‐FMK and 5 μM rottlerin (a PKCδ inhibitor) also significantly attenuated MMT‐induced DNA fragmentation. Furthermore, overexpression of either the kinase inactive dominant negative PKCδK376R mutant or the caspase cleavage resistant PKCδD327A 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 PKCδ in MMT‐induced dopaminergic degeneration and suggest that PKCδ may serve as an attractive therapeutic target in Parkinson‐related neurological diseases.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Anantharam, V" sort="Anantharam, V" uniqKey="Anantharam V" first="V" last="Anantharam">V. Anantharam</name></noRegion><name sortKey="Kanthasamy, A" sort="Kanthasamy, A" uniqKey="Kanthasamy A" first="A" last="Kanthasamy">A. Kanthasamy</name><name sortKey="Kanthasamy, A G" sort="Kanthasamy, A G" uniqKey="Kanthasamy A" first="A G" last="Kanthasamy">A G Kanthasamy</name><name sortKey="Kitazawa, M" sort="Kitazawa, M" uniqKey="Kitazawa M" first="M" last="Kitazawa">M. Kitazawa</name><name sortKey="Latchoumycandane, C" sort="Latchoumycandane, C" uniqKey="Latchoumycandane C" first="C" last="Latchoumycandane">C. Latchoumycandane</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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