Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis
Identifieur interne : 001E48 ( Main/Corpus ); précédent : 001E47; suivant : 001E49Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis
Auteurs : Houbo Jiang ; Yong Ren ; Jinghui Zhao ; Jian FengSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2004-08-15.
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 H2O2 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.
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DOI: 10.1093/hmg/ddh180
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Mol. Genet.</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2004-08-15">2004-08-15</date><biblScope unit="volume">13</biblScope><biblScope unit="issue">16</biblScope><biblScope unit="page" from="1745">1745</biblScope><biblScope unit="page" to="1754">1754</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">4FB52DE17CBEC0FC1FE74CA2EFB78751AC36BD76</idno><idno type="DOI">10.1093/hmg/ddh180</idno><idno type="local">ddh180</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 H2O2 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.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Houbo Jiang</name><affiliations><json:string>Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA</json:string></affiliations></json:item><json:item><name>Yong Ren</name><affiliations><json:string>Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA</json:string></affiliations></json:item><json:item><name>Jinghui Zhao</name><affiliations><json:string>Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA</json:string></affiliations></json:item><json:item><name>Jian Feng</name><affiliations><json:string>Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA</json:string><json:string>E-mail: jianfeng@buffalo.edu</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Article</value></json:item></subject><language><json:string>eng</json:string></language><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 H2O2 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. 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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 H2O2 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. 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Mol. Genet.</abbrev-journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">ddh180</article-id><article-id pub-id-type="doi">10.1093/hmg/ddh180</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Houbo</given-names></name></contrib><contrib contrib-type="author"><name><surname>Ren</surname><given-names>Yong</given-names></name></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Jinghui</given-names></name></contrib><contrib contrib-type="author"><name><surname>Feng</surname><given-names>Jian</given-names></name><xref rid="COR1">*</xref></contrib><aff>Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA</aff></contrib-group><author-notes><corresp id="COR1"><label>*</label>To whom correspondence should be addressed at: Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY 14214, USA. Tel: +1 7168292345; Fax: +1 7168292699; Email: <ext-link xlink:href="jianfeng@buffalo.edu" ext-link-type="email">jianfeng@buffalo.edu</ext-link></corresp></author-notes><pub-date pub-type="epub"><day>15</day><month>06</month><year>2004</year></pub-date><pub-date pub-type="ppub"><day>15</day><month>08</month><year>2004</year></pub-date><volume>13</volume><issue>16</issue><fpage>1745</fpage><lpage>1754</lpage><history><date date-type="accepted"><day>1</day><month>06</month><year>2004</year></date><date date-type="received"><day>8</day><month>04</month><year>2004</year></date></history><permissions><copyright-statement>Human Molecular Genetics, Vol. 13, No. 16 © Oxford University Press 2004; all rights reserved</copyright-statement><copyright-year>2004</copyright-year></permissions><abstract xml:lang="en"><p>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<sub>2</sub>O<sub>2</sub> 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.</p></abstract><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>1745</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>Article</meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis</title></titleInfo><name type="personal"><namePart type="given">Houbo</namePart><namePart type="family">Jiang</namePart><affiliation>Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yong</namePart><namePart type="family">Ren</namePart><affiliation>Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jinghui</namePart><namePart type="family">Zhao</namePart><affiliation>Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jian</namePart><namePart type="family">Feng</namePart><affiliation>Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA</affiliation><affiliation>E-mail: jianfeng@buffalo.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2004-08-15</dateIssued><dateCreated encoding="w3cdtf">2004-06-15</dateCreated><copyrightDate encoding="w3cdtf">2004</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">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 H2O2 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.</abstract><note type="author-notes">*To whom correspondence should be addressed at: Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY 14214, USA. 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|texte= Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis
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