Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease
Identifieur interne : 000304 ( Pmc/Curation ); précédent : 000303; suivant : 000305Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease
Auteurs : Christophe Lo Bianco [Suisse] ; Bernard L. Schneider [Suisse] ; Matthias Bauer [Suisse] ; Ali Sajadi [Suisse] ; Alexis Brice [France] ; Takeshi Iwatsubo [Japon] ; Patrick Aebischer [Suisse]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2004.
Abstract
Parkinson's disease (PD) is characterized by a progressive loss of midbrain dopamine neurons and the presence of cytoplasmic inclusions called Lewy bodies. Mutations in several genes including α-synuclein and parkin have been linked to familial PD. The loss of parkin's E3-ligase activity leads to dopaminergic neuronal degeneration in early-onset autosomal recessive juvenile parkinsonism, suggesting a key role of parkin for dopamine neuron survival. To evaluate the potential neuroprotective role of parkin in the pathogenesis of PD, we tested whether overexpression of wild-type rat parkin could protect against the toxicity of mutated human A30P α-synuclein in a rat lentiviral model of PD. Animals overexpressing parkin showed significant reductions in α-synuclein-induced neuropathology, including preservation of tyrosine hydroxylase-positive cell bodies in the substantia nigra and sparing of tyrosine hydroxylase-positive nerve terminals in the striatum. The parkin-mediated neuroprotection was associated with an increase in hyperphosphorylated α-synuclein inclusions, suggesting a key role for parkin in the genesis of Lewy bodies. These results indicate that parkin gene therapy may represent a promising candidate treatment for PD.
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DOI: 10.1073/pnas.0405313101
PubMed: 15576511
PubMed Central: 536019
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Schneider</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne</wicri:regionArea></affiliation></author><author><name sortKey="Bauer, Matthias" sort="Bauer, Matthias" uniqKey="Bauer M" first="Matthias" last="Bauer">Matthias Bauer</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne</wicri:regionArea></affiliation></author><author><name sortKey="Sajadi, Ali" sort="Sajadi, Ali" uniqKey="Sajadi A" first="Ali" last="Sajadi">Ali Sajadi</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne</wicri:regionArea></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0x96db120.0x9cedd28">Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpétrière, 75651 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpétrière, 75651 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Iwatsubo, Takeshi" sort="Iwatsubo, Takeshi" uniqKey="Iwatsubo T" first="Takeshi" last="Iwatsubo">Takeshi Iwatsubo</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033</wicri:regionArea></affiliation></author><author><name sortKey="Aebischer, Patrick" sort="Aebischer, Patrick" uniqKey="Aebischer P" first="Patrick" last="Aebischer">Patrick Aebischer</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">15576511</idno><idno type="pmc">536019</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC536019</idno><idno type="RBID">PMC:536019</idno><idno type="doi">10.1073/pnas.0405313101</idno><date when="2004">2004</date><idno type="wicri:Area/Pmc/Corpus">000306</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000306</idno><idno type="wicri:Area/Pmc/Curation">000304</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000304</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease</title><author><name sortKey="Lo Bianco, Christophe" sort="Lo Bianco, Christophe" uniqKey="Lo Bianco C" first="Christophe" last="Lo Bianco">Christophe Lo Bianco</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne</wicri:regionArea></affiliation></author><author><name sortKey="Schneider, Bernard L" sort="Schneider, Bernard L" uniqKey="Schneider B" first="Bernard L." last="Schneider">Bernard L. Schneider</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne</wicri:regionArea></affiliation></author><author><name sortKey="Bauer, Matthias" sort="Bauer, Matthias" uniqKey="Bauer M" first="Matthias" last="Bauer">Matthias Bauer</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne</wicri:regionArea></affiliation></author><author><name sortKey="Sajadi, Ali" sort="Sajadi, Ali" uniqKey="Sajadi A" first="Ali" last="Sajadi">Ali Sajadi</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne</wicri:regionArea></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0x96db120.0x9cedd28">Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpétrière, 75651 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpétrière, 75651 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Iwatsubo, Takeshi" sort="Iwatsubo, Takeshi" uniqKey="Iwatsubo T" first="Takeshi" last="Iwatsubo">Takeshi Iwatsubo</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033</wicri:regionArea></affiliation></author><author><name sortKey="Aebischer, Patrick" sort="Aebischer, Patrick" uniqKey="Aebischer P" first="Patrick" last="Aebischer">Patrick Aebischer</name><affiliation wicri:level="1"><nlm:aff id="N0x96db120.0x9cedd28">Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne</wicri:regionArea></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 characterized by a progressive loss of midbrain dopamine neurons and the presence of cytoplasmic inclusions called Lewy bodies. Mutations in several genes including α-synuclein and parkin have been linked to familial PD. The loss of parkin's E3-ligase activity leads to dopaminergic neuronal degeneration in early-onset autosomal recessive juvenile parkinsonism, suggesting a key role of parkin for dopamine neuron survival. To evaluate the potential neuroprotective role of parkin in the pathogenesis of PD, we tested whether overexpression of wild-type rat parkin could protect against the toxicity of mutated human A30P α-synuclein in a rat lentiviral model of PD. Animals overexpressing parkin showed significant reductions in α-synuclein-induced neuropathology, including preservation of tyrosine hydroxylase-positive cell bodies in the substantia nigra and sparing of tyrosine hydroxylase-positive nerve terminals in the striatum. The parkin-mediated neuroprotection was associated with an increase in hyperphosphorylated α-synuclein inclusions, suggesting a key role for parkin in the genesis of Lewy bodies. These results indicate that parkin gene therapy may represent a promising candidate treatment for 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">15576511</article-id><article-id pub-id-type="pmc">536019</article-id><article-id pub-id-type="publisher-id">010117510</article-id><article-id pub-id-type="doi">10.1073/pnas.0405313101</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>Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lo Bianco</surname><given-names>Christophe</given-names></name><xref ref-type="aff" rid="N0x96db120.0x9cedd28">*</xref></contrib><contrib contrib-type="author"><name><surname>Schneider</surname><given-names>Bernard L.</given-names></name><xref ref-type="aff" rid="N0x96db120.0x9cedd28">*</xref><xref ref-type="fn" rid="fn1">†</xref></contrib><contrib contrib-type="author"><name><surname>Bauer</surname><given-names>Matthias</given-names></name><xref ref-type="aff" rid="N0x96db120.0x9cedd28">*</xref></contrib><contrib contrib-type="author"><name><surname>Sajadi</surname><given-names>Ali</given-names></name><xref ref-type="aff" rid="N0x96db120.0x9cedd28">*</xref></contrib><contrib contrib-type="author"><name><surname>Brice</surname><given-names>Alexis</given-names></name><xref ref-type="aff" rid="N0x96db120.0x9cedd28">‡</xref></contrib><contrib contrib-type="author"><name><surname>Iwatsubo</surname><given-names>Takeshi</given-names></name><xref ref-type="aff" rid="N0x96db120.0x9cedd28">§</xref></contrib><contrib contrib-type="author"><name><surname>Aebischer</surname><given-names>Patrick</given-names></name><xref ref-type="aff" rid="N0x96db120.0x9cedd28">*</xref><xref ref-type="corresp" rid="cor1">¶</xref></contrib></contrib-group><aff id="N0x96db120.0x9cedd28"><label>*</label>Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;<label>‡</label>Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpétrière, 75651 Paris, France; and<label>§</label>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan</aff><author-notes><fn id="cor1"><label>¶</label><p> To whom correspondence should be addressed at: Institute of Neuroscience, SG-AAB 132, Swiss Federal institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. E-mail: <email>patrick.aebischer@epfl.ch</email>. </p></fn><fn id="fn1"><label>†</label><p>Present address: Waisman Center, University of Wisconsin, Madison, WI 53705.</p></fn><fn><p>Edited by Fred H. Gage, The Salk Institute for Biological Studies, San Diego, CA, and approved October 29, 2004</p></fn></author-notes><pub-date pub-type="ppub"><day>14</day><month>12</month><year>2004</year></pub-date><pub-date pub-type="epub"><day>2</day><month>12</month><year>2004</year></pub-date><volume>101</volume><issue>50</issue><fpage>17510</fpage><lpage>17515</lpage><history><date date-type="received"><day>22</day><month>7</month><year>2004</year></date></history><copyright-statement>Copyright © 2004, The National Academy of Sciences</copyright-statement><copyright-year>2004</copyright-year><abstract><p>Parkinson's disease (PD) is characterized by a progressive loss of midbrain dopamine neurons and the presence of cytoplasmic inclusions called Lewy bodies. Mutations in several genes including α-synuclein and parkin have been linked to familial PD. The loss of parkin's E3-ligase activity leads to dopaminergic neuronal degeneration in early-onset autosomal recessive juvenile parkinsonism, suggesting a key role of parkin for dopamine neuron survival. To evaluate the potential neuroprotective role of parkin in the pathogenesis of PD, we tested whether overexpression of wild-type rat parkin could protect against the toxicity of mutated human A30P α-synuclein in a rat lentiviral model of PD. Animals overexpressing parkin showed significant reductions in α-synuclein-induced neuropathology, including preservation of tyrosine hydroxylase-positive cell bodies in the substantia nigra and sparing of tyrosine hydroxylase-positive nerve terminals in the striatum. The parkin-mediated neuroprotection was associated with an increase in hyperphosphorylated α-synuclein inclusions, suggesting a key role for parkin in the genesis of Lewy bodies. These results indicate that parkin gene therapy may represent a promising candidate treatment for PD.</p></abstract><kwd-group><kwd>gene therapy</kwd><kwd>lentivirus</kwd><kwd>neurodegenerative disease</kwd><kwd>Lewy body</kwd><kwd>neuroprotection</kwd></kwd-group></article-meta><notes><fn-group><fn><p>Author contributions: C.L. and P.A. designed research; C.L., B.L.S., A.B., and T.I. performed research; C.L., B.L.S., M.B., and A.S. analyzed data; and C.L. and P.A. wrote the paper.</p></fn><fn><p>This paper was submitted directly (Track II) to the PNAS office.</p></fn><fn><p>Abbreviations: AR-JP, autosomal recessive juvenile parkinsonism; PD, Parkinson's disease; TH, tyrosine hydroxylase; TH-IR, TH-immunoreactive; YFP, yellow fluorescent protein.</p></fn></fn-group></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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