Blockade of PKCδ Proteolytic Activation by Loss of Function Mutants Rescues Mesencephalic Dopaminergic Neurons from Methylcyclopentadienyl Manganese Tricarbonyl (MMT)--Induced Apoptotic Cell Death.
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| Title: | Blockade of PKCδ Proteolytic Activation by Loss of Function Mutants Rescues Mesencephalic Dopaminergic Neurons from Methylcyclopentadienyl Manganese Tricarbonyl (MMT)--Induced Apoptotic Cell Death. |
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| Authors: | ANANTHARAM, V1 (AUTHOR), KITAZAWA, M1 (AUTHOR), LATCHOUMYCANDANE, C1 (AUTHOR), KANTHASAMY, A1 (AUTHOR), KANTHASAMY, A G1 (AUTHOR) |
| Source: | Annals of the New York Academy of Sciences. 2004, Vol. 1035 Issue 1, p271-289. 19p. |
| Subjects: | Protein kinases, Neurons, Manganese compounds, Apoptosis, Parkinson's disease |
| 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 cellsignaling 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 mitochondrialdependent 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 ZDEVD- 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 PKC δin MMT-induced dopaminergic degeneration and suggest that PKCδ may serve as an attractive therapeutic target in Parkinson-related neurological diseases. [ABSTRACT FROM AUTHOR] |
| Copyright of Annals of the New York Academy of Sciences is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Header | DbId: egs DbLabel: Engineering Source An: 25195428 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Blockade of PKCδ Proteolytic Activation by Loss of Function Mutants Rescues Mesencephalic Dopaminergic Neurons from Methylcyclopentadienyl Manganese Tricarbonyl (MMT)--Induced Apoptotic Cell Death. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22ANANTHARAM%2C+V%22">ANANTHARAM, V</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22KITAZAWA%2C+M%22">KITAZAWA, M</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22LATCHOUMYCANDANE%2C+C%22">LATCHOUMYCANDANE, C</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22KANTHASAMY%2C+A%22">KANTHASAMY, A</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22KANTHASAMY%2C+A+G%22">KANTHASAMY, A G</searchLink><relatesTo>1</relatesTo> (AUTHOR) – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Annals+of+the+New+York+Academy+of+Sciences%22">Annals of the New York Academy of Sciences</searchLink>. 2004, Vol. 1035 Issue 1, p271-289. 19p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Protein+kinases%22">Protein kinases</searchLink><br /><searchLink fieldCode="DE" term="%22Neurons%22">Neurons</searchLink><br /><searchLink fieldCode="DE" term="%22Manganese+compounds%22">Manganese compounds</searchLink><br /><searchLink fieldCode="DE" term="%22Apoptosis%22">Apoptosis</searchLink><br /><searchLink fieldCode="DE" term="%22Parkinson's+disease%22">Parkinson's disease</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: 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 cellsignaling 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 mitochondrialdependent 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 ZDEVD- 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 PKC δin MMT-induced dopaminergic degeneration and suggest that PKCδ may serve as an attractive therapeutic target in Parkinson-related neurological diseases. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Annals of the New York Academy of Sciences is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1196/annals.1332.017 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 19 StartPage: 271 Subjects: – SubjectFull: Protein kinases Type: general – SubjectFull: Neurons Type: general – SubjectFull: Manganese compounds Type: general – SubjectFull: Apoptosis Type: general – SubjectFull: Parkinson's disease Type: general Titles: – TitleFull: Blockade of PKCδ Proteolytic Activation by Loss of Function Mutants Rescues Mesencephalic Dopaminergic Neurons from Methylcyclopentadienyl Manganese Tricarbonyl (MMT)--Induced Apoptotic Cell Death. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: ANANTHARAM, V – PersonEntity: Name: NameFull: KITAZAWA, M – PersonEntity: Name: NameFull: LATCHOUMYCANDANE, C – PersonEntity: Name: NameFull: KANTHASAMY, A – PersonEntity: Name: NameFull: KANTHASAMY, A G IsPartOfRelationships: – BibEntity: Dates: – D: 07 M: 12 Text: 2004 Type: published Y: 2004 Identifiers: – Type: issn-print Value: 00778923 Numbering: – Type: volume Value: 1035 – Type: issue Value: 1 Titles: – TitleFull: Annals of the New York Academy of Sciences Type: main |
| ResultId | 1 |
