JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease
Identifieur interne : 000303 ( Pmc/Curation ); précédent : 000302; suivant : 000304JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease
Auteurs : Stéphane Hunot ; Miquel Vila ; Peter Teismann ; Roger J. Davis [États-Unis] ; Etienne C. Hirsch ; Serge Przedborski [États-Unis] ; Pasko Rakic [États-Unis] ; Richard A. FlavellSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2004.
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopamine-containing neurons, but the molecular pathways underlying its pathogenesis remain uncertain. Here, we show that by eliminating c-Jun N-terminal kinases (JNKs) we can prevent neurodegeneration and improve motor function in an animal model of PD. First, we found that c-Jun is activated in dopaminergic neurons from PD patients and in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model of PD. Examination of various JNK-deficient mice shows that both JNK2 and JNK3, but not JNK1, are required for MPTP-induced c-Jun activation and dopaminergic cell demise. Furthermore, we have identified cyclooxygenase (COX) 2 as a molecular target of JNK activation and demonstrated that COX-2 is indispensable for MPTP-induced dopaminergic cell death. Our data revealed that JNK2- and JNK3-induced COX-2 may be a principle pathway responsible for neurodegeneration in PD.
Url:
DOI: 10.1073/pnas.0307453101
PubMed: 14704277
PubMed Central: 327205
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Stéphane Hunot<affiliation><nlm:aff id="N0x8d186f0.0x8a8d538">Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpêtrière, 75013 Paris, France; Departments of</nlm:aff><wicri:noCountry code="subfield">France; Departments of</wicri:noCountry></affiliation><affiliation><nlm:aff id="N0x8d186f0.0x8a8d538">Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpêtrière, 75013 Paris, France; Departments of</nlm:aff><wicri:noCountry code="subfield">France; Departments of</wicri:noCountry></affiliation>Le document en format XML
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Davis</name><affiliation wicri:level="2"><nlm:aff id="N0x8d186f0.0x8a8d538">Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester</wicri:cityArea></affiliation><affiliation><nlm:aff wicri:cut=", and" id="N0x8d186f0.0x8a8d538">Howard Hughes Medical Institute</nlm:aff></affiliation></author><author><name sortKey="Hirsch, Etienne C" sort="Hirsch, Etienne C" uniqKey="Hirsch E" first="Etienne C." last="Hirsch">Etienne C. 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Flavell</name><affiliation><nlm:aff id="N0x8d186f0.0x8a8d538">Section of Immunobiology,</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="N0x8d186f0.0x8a8d538">Howard Hughes Medical Institute</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">14704277</idno><idno type="pmc">327205</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC327205</idno><idno type="RBID">PMC:327205</idno><idno type="doi">10.1073/pnas.0307453101</idno><date when="2004">2004</date><idno type="wicri:Area/Pmc/Corpus">000305</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000305</idno><idno type="wicri:Area/Pmc/Curation">000303</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000303</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease</title><author><name sortKey="Hunot, Stephane" sort="Hunot, Stephane" uniqKey="Hunot S" first="Stéphane" last="Hunot">Stéphane Hunot</name><affiliation><nlm:aff id="N0x8d186f0.0x8a8d538">Section of Immunobiology,</nlm:aff></affiliation><affiliation><nlm:aff id="N0x8d186f0.0x8a8d538">Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpêtrière, 75013 Paris, France; Departments of</nlm:aff><wicri:noCountry code="subfield">France; Departments of</wicri:noCountry></affiliation></author><author><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name><affiliation><nlm:aff wicri:cut=" and" id="N0x8d186f0.0x8a8d538">Neurology</nlm:aff></affiliation></author><author><name sortKey="Teismann, Peter" sort="Teismann, Peter" uniqKey="Teismann P" first="Peter" last="Teismann">Peter Teismann</name><affiliation><nlm:aff wicri:cut=" and" id="N0x8d186f0.0x8a8d538">Neurology</nlm:aff></affiliation></author><author><name sortKey="Davis, Roger J" sort="Davis, Roger J" uniqKey="Davis R" first="Roger J." last="Davis">Roger J. Davis</name><affiliation wicri:level="2"><nlm:aff id="N0x8d186f0.0x8a8d538">Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester</wicri:cityArea></affiliation><affiliation><nlm:aff wicri:cut=", and" id="N0x8d186f0.0x8a8d538">Howard Hughes Medical Institute</nlm:aff></affiliation></author><author><name sortKey="Hirsch, Etienne C" sort="Hirsch, Etienne C" uniqKey="Hirsch E" first="Etienne C." last="Hirsch">Etienne C. Hirsch</name><affiliation><nlm:aff id="N0x8d186f0.0x8a8d538">Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpêtrière, 75013 Paris, France; Departments of</nlm:aff><wicri:noCountry code="subfield">France; Departments of</wicri:noCountry></affiliation></author><author><name sortKey="Przedborski, Serge" sort="Przedborski, Serge" uniqKey="Przedborski S" first="Serge" last="Przedborski">Serge Przedborski</name><affiliation><nlm:aff wicri:cut=" and" id="N0x8d186f0.0x8a8d538">Neurology</nlm:aff></affiliation><affiliation wicri:level="2"><nlm:aff wicri:cut="; and" id="N0x8d186f0.0x8a8d538">Pathology and the Center for Neurobiology and Behavior, Columbia University, New York, NY 10032</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Pathology and the Center for Neurobiology and Behavior, Columbia University, New York</wicri:cityArea></affiliation></author><author><name sortKey="Rakic, Pasko" sort="Rakic, Pasko" uniqKey="Rakic P" first="Pasko" last="Rakic">Pasko Rakic</name><affiliation wicri:level="2"><nlm:aff id="N0x8d186f0.0x8a8d538">Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06520;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Connecticut</region></placeName><wicri:cityArea>Department of Neurobiology, Yale University School of Medicine, New Haven</wicri:cityArea></affiliation></author><author><name sortKey="Flavell, Richard A" sort="Flavell, Richard A" uniqKey="Flavell R" first="Richard A." last="Flavell">Richard A. Flavell</name><affiliation><nlm:aff id="N0x8d186f0.0x8a8d538">Section of Immunobiology,</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="N0x8d186f0.0x8a8d538">Howard Hughes Medical Institute</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopamine-containing neurons, but the molecular pathways underlying its pathogenesis remain uncertain. Here, we show that by eliminating c-Jun N-terminal kinases (JNKs) we can prevent neurodegeneration and improve motor function in an animal model of PD. First, we found that c-Jun is activated in dopaminergic neurons from PD patients and in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model of PD. Examination of various JNK-deficient mice shows that both JNK2 and JNK3, but not JNK1, are required for MPTP-induced c-Jun activation and dopaminergic cell demise. Furthermore, we have identified cyclooxygenase (COX) 2 as a molecular target of JNK activation and demonstrated that COX-2 is indispensable for MPTP-induced dopaminergic cell death. Our data revealed that JNK2- and JNK3-induced COX-2 may be a principle pathway responsible for neurodegeneration in PD.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="publisher-id">pnas</journal-id><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">14704277</article-id><article-id pub-id-type="pmc">327205</article-id><article-id pub-id-type="publisher-id">1010665</article-id><article-id pub-id-type="doi">10.1073/pnas.0307453101</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Neuroscience</subject></subj-group></subj-group></article-categories><title-group><article-title>JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hunot</surname><given-names>Stéphane</given-names></name><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">*</xref><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">†</xref></contrib><contrib contrib-type="author"><name><surname>Vila</surname><given-names>Miquel</given-names></name><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">‡</xref></contrib><contrib contrib-type="author"><name><surname>Teismann</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">‡</xref></contrib><contrib contrib-type="author"><name><surname>Davis</surname><given-names>Roger J.</given-names></name><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">§</xref><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">¶</xref></contrib><contrib contrib-type="author"><name><surname>Hirsch</surname><given-names>Etienne C.</given-names></name><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">†</xref></contrib><contrib contrib-type="author"><name><surname>Przedborski</surname><given-names>Serge</given-names></name><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">‡</xref><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">∥</xref></contrib><contrib contrib-type="author"><name><surname>Rakic</surname><given-names>Pasko</given-names></name><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">**</xref></contrib><contrib contrib-type="author"><name><surname>Flavell</surname><given-names>Richard A.</given-names></name><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">*</xref><xref ref-type="aff" rid="N0x8d186f0.0x8a8d538">¶</xref><xref ref-type="corresp" rid="cor1">††</xref></contrib></contrib-group><aff id="N0x8d186f0.0x8a8d538"><label>*</label>Section of Immunobiology,<label>¶</label>Howard Hughes Medical Institute, and<label>**</label>Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06520;<label>†</label>Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpêtrière, 75013 Paris, France; Departments of<label>‡</label>Neurology and<label>∥</label>Pathology and the Center for Neurobiology and Behavior, Columbia University, New York, NY 10032; and<label>§</label>Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605</aff><author-notes><fn id="cor1"><label>††</label><p> To whom correspondence should be addressed at: Yale University School of Medicine, The Anlyan Center S-569, 300 Cedar Street, New Haven, CT 06520. E-mail: <email>richard.flavell@yale.edu</email>. </p></fn><fn><p>Contributed by Richard A. Flavell, November 10, 2003</p></fn></author-notes><pub-date pub-type="ppub"><day>13</day><month>1</month><year>2004</year></pub-date><pub-date pub-type="epub"><day>2</day><month>1</month><year>2004</year></pub-date><volume>101</volume><issue>2</issue><fpage>665</fpage><lpage>670</lpage><copyright-statement>Copyright © 2004, The National Academy of Sciences</copyright-statement><copyright-year>2004</copyright-year><abstract><p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopamine-containing neurons, but the molecular pathways underlying its pathogenesis remain uncertain. Here, we show that by eliminating c-Jun N-terminal kinases (JNKs) we can prevent neurodegeneration and improve motor function in an animal model of PD. First, we found that c-Jun is activated in dopaminergic neurons from PD patients and in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model of PD. Examination of various JNK-deficient mice shows that both JNK2 and JNK3, but not JNK1, are required for MPTP-induced c-Jun activation and dopaminergic cell demise. Furthermore, we have identified cyclooxygenase (COX) 2 as a molecular target of JNK activation and demonstrated that COX-2 is indispensable for MPTP-induced dopaminergic cell death. Our data revealed that JNK2- and JNK3-induced COX-2 may be a principle pathway responsible for neurodegeneration in PD.</p></abstract></article-meta><notes><fn-group><fn><p>Abbreviations: COX, cyclooxygenase; GFAP, glial fibrillary acidic protein; JNK, c-Jun N-terminal kinase; MAC-1, macrophage antigen complex 1; MPP<sup>+</sup>, 1-methyl-4-phenylpyridinium ion; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson's disease; SN, substantia nigra; SNpc, SN pars compacta; TH, tyrosine hydroxylase.</p></fn></fn-group></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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