FAS-Dependent Cell Death in α-Synuclein Transgenic Oligodendrocyte Models of Multiple System Atrophy
Identifieur interne : 000812 ( Pmc/Curation ); précédent : 000811; suivant : 000813FAS-Dependent Cell Death in α-Synuclein Transgenic Oligodendrocyte Models of Multiple System Atrophy
Auteurs : Christine L. Kragh [Danemark] ; Gwenaëlle Fillon [Allemagne] ; Amanda Gysbers [Australie] ; Hanne D. Hansen [Allemagne] ; Manuela Neumann [Suisse] ; Christiane Richter-Landsberg [Allemagne] ; Christian Haass [Allemagne] ; Bernard Zalc [France] ; Catherine Lubetzki [France] ; Wei-Ping Gai [Australie] ; Glenda M. Halliday [Australie] ; Philipp J. Kahle [Allemagne] ; Poul H. Jensen [Danemark]Source :
- PLoS ONE [ 1932-6203 ] ; 2013.
Abstract
Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention.
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DOI: 10.1371/journal.pone.0055243
PubMed: 23372841
PubMed Central: 3555893
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Kragh</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Biomedicine, Aarhus University, Aarhus, Denmark</addr-line></nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Biomedicine, Aarhus University, Aarhus</wicri:regionArea></affiliation></author><author><name sortKey="Fillon, Gwenaelle" sort="Fillon, Gwenaelle" uniqKey="Fillon G" first="Gwenaëlle" last="Fillon">Gwenaëlle Fillon</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilians University, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilians University, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Gysbers, Amanda" sort="Gysbers, Amanda" uniqKey="Gysbers A" first="Amanda" last="Gysbers">Amanda Gysbers</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Neuroscience Research Australia and University of New South Wales, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Neuroscience Research Australia and University of New South Wales, Sydney, New South Wales</wicri:regionArea></affiliation></author><author><name sortKey="Hansen, Hanne D" sort="Hansen, Hanne D" uniqKey="Hansen H" first="Hanne D." last="Hansen">Hanne D. Hansen</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen</wicri:regionArea></affiliation></author><author><name sortKey="Neumann, Manuela" sort="Neumann, Manuela" uniqKey="Neumann M" first="Manuela" last="Neumann">Manuela Neumann</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Institute for Neuropathology, University of Zürich, Zürich, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute for Neuropathology, University of Zürich, Zürich</wicri:regionArea></affiliation></author><author><name sortKey="Richter Landsberg, Christiane" sort="Richter Landsberg, Christiane" uniqKey="Richter Landsberg C" first="Christiane" last="Richter-Landsberg">Christiane Richter-Landsberg</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Department of Biology, University of Oldenburg, Oldenburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Biology, University of Oldenburg, Oldenburg</wicri:regionArea></affiliation></author><author><name sortKey="Haass, Christian" sort="Haass, Christian" uniqKey="Haass C" first="Christian" last="Haass">Christian Haass</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilians University, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilians University, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Zalc, Bernard" sort="Zalc, Bernard" uniqKey="Zalc B" first="Bernard" last="Zalc">Bernard Zalc</name><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Université Pierre et Marie Curie, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Université Pierre et Marie Curie, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Lubetzki, Catherine" sort="Lubetzki, Catherine" uniqKey="Lubetzki C" first="Catherine" last="Lubetzki">Catherine Lubetzki</name><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Université Pierre et Marie Curie, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Université Pierre et Marie Curie, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Gai, Wei Ping" sort="Gai, Wei Ping" uniqKey="Gai W" first="Wei-Ping" last="Gai">Wei-Ping Gai</name><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>Department of Human Physiology and Centre for Neuroscience, Flinders University School of Medicine, Bedford Park, South Australia, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Human Physiology and Centre for Neuroscience, Flinders University School of Medicine, Bedford Park, South Australia</wicri:regionArea></affiliation></author><author><name sortKey="Halliday, Glenda M" sort="Halliday, Glenda M" uniqKey="Halliday G" first="Glenda M." last="Halliday">Glenda M. Halliday</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Neuroscience Research Australia and University of New South Wales, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Neuroscience Research Australia and University of New South Wales, Sydney, New South Wales</wicri:regionArea></affiliation></author><author><name sortKey="Kahle, Philipp J" sort="Kahle, Philipp J" uniqKey="Kahle P" first="Philipp J." last="Kahle">Philipp J. Kahle</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9"><addr-line>German Center for Neurodegenerative Diseases, Tübingen, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Neurodegenerative Diseases, Tübingen</wicri:regionArea></affiliation></author><author><name sortKey="Jensen, Poul H" sort="Jensen, Poul H" uniqKey="Jensen P" first="Poul H." last="Jensen">Poul H. Jensen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Biomedicine, Aarhus University, Aarhus, Denmark</addr-line></nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Biomedicine, Aarhus University, Aarhus</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Arima, K" uniqKey="Arima K">K Arima</name></author><author><name sortKey="Ueda, K" uniqKey="Ueda K">K Ueda</name></author><author><name sortKey="Sunohara, N" uniqKey="Sunohara N">N Sunohara</name></author><author><name sortKey="Hirai, S" uniqKey="Hirai S">S Hirai</name></author><author><name sortKey="Izumiyama, Y" uniqKey="Izumiyama Y">Y Izumiyama</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tu, Ph" uniqKey="Tu P">PH Tu</name></author><author><name sortKey="Galvin, Je" uniqKey="Galvin J">JE Galvin</name></author><author><name sortKey="Baba, M" uniqKey="Baba M">M Baba</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23372841</article-id><article-id pub-id-type="pmc">3555893</article-id><article-id pub-id-type="publisher-id">PONE-D-12-14569</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0055243</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immunologic Techniques</subject><subj-group><subject>Immunoassays</subject></subj-group></subj-group></subj-group><subj-group><subject>Model Organisms</subject><subj-group><subject>Animal Models</subject><subj-group><subject>Rat</subject></subj-group></subj-group></subj-group><subj-group><subject>Neuroscience</subject><subj-group><subject>Molecular Neuroscience</subject><subj-group><subject>Signaling Pathways</subject></subj-group></subj-group><subj-group><subject>Cellular Neuroscience</subject><subject>Neurobiology of Disease and Regeneration</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject><subj-group><subject>Neurology</subject><subj-group><subject>Cerebellar Disorders</subject><subject>Movement Disorders</subject><subject>Neurodegenerative Diseases</subject><subject>Parkinson Disease</subject></subj-group></subj-group></subj-group></article-categories><title-group><article-title>FAS-Dependent Cell Death in α-Synuclein Transgenic Oligodendrocyte Models of Multiple System Atrophy</article-title><alt-title alt-title-type="running-head">FAS in Multiple System Atrophy</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Kragh</surname><given-names>Christine L.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Fillon</surname><given-names>Gwenaëlle</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>¤a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gysbers</surname><given-names>Amanda</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hansen</surname><given-names>Hanne D.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="author-notes" rid="fn2"><sup>¤b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Neumann</surname><given-names>Manuela</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Richter-Landsberg</surname><given-names>Christiane</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Haass</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zalc</surname><given-names>Bernard</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lubetzki</surname><given-names>Catherine</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gai</surname><given-names>Wei-Ping</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Halliday</surname><given-names>Glenda M.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kahle</surname><given-names>Philipp J.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="aff" rid="aff9"><sup>9</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jensen</surname><given-names>Poul H.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Department of Biomedicine, Aarhus University, Aarhus, Denmark</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilians University, Munich, Germany</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Neuroscience Research Australia and University of New South Wales, Sydney, New South Wales, Australia</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Institute for Neuropathology, University of Zürich, Zürich, Switzerland</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Department of Biology, University of Oldenburg, Oldenburg, Germany</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Université Pierre et Marie Curie, Paris, France</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Department of Human Physiology and Centre for Neuroscience, Flinders University School of Medicine, Bedford Park, South Australia, Australia</addr-line></aff><aff id="aff9"><label>9</label><addr-line>German Center for Neurodegenerative Diseases, Tübingen, Germany</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Smith</surname><given-names>Wanli</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Maryland School of Pharmacy, United States of America</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>phj@biokemi.au.dk</email> (PHJ); <email>Philipp.Kahle@uni-tuebingen.de</email> (PJK)</corresp><fn fn-type="conflict"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: CLK GF MN CH CL WPG GMH PJK PHJ. Performed the experiments: CLK GF AG HDH MN WPG. Analyzed the data: CLK GF MN WPG GMH PJK PHJ. Contributed reagents/materials/analysis tools: CH BZ CRL CL WPG GMH PHJ PJK. Wrote the paper: CLK GF GMH PJK PHJ.</p></fn><fn id="fn1" fn-type="current-aff"><label>¤a</label><p>Current address: F. Hoffmann – La Roche Ltd, Basel, Switzerland</p></fn><fn id="fn2" fn-type="current-aff"><label>¤b</label><p>Current address: Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark</p></fn></author-notes><pub-date pub-type="collection"><year>2013</year></pub-date><pub-date pub-type="epub"><day>25</day><month>1</month><year>2013</year></pub-date><volume>8</volume><issue>1</issue><elocation-id>e55243</elocation-id><history><date date-type="received"><day>21</day><month>5</month><year>2012</year></date><date date-type="accepted"><day>27</day><month>12</month><year>2012</year></date></history><permissions><copyright-year>2013</copyright-year><copyright-holder>Kragh et al</copyright-holder><license><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention.</p></abstract><funding-group><funding-statement>This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 241791 (MEFOPA), n° 238316 (Neurasync), the Lundbeck Foundation, the Deutsche Forschungsgemeinschaft (SFB 596, project A1), the European consortium to develop PD gene therapy (NEUROPARK), the Fondation pour la Recherche Médicale, The Danish Medical Research Council, Aarhus University, the Foundation of 1984 for treatment of Parkinson disease, Federal Ministry of Education and Research (Project-No. 01GI0299). GMH and WPG have NHMRC Research Fellowships (630434 & 535014). Human brain samples were received thanks to support from the National Health and Medical Research Council of Australia (NHMRC), Neuroscience Research Australia, the University of New South Wales, the Schizophrenia Research Institute, the National Institute of Alcohol Abuse and Alcoholism (NIH (NIAAA) R24AA012725, University of Sydney and the Flinders Medical Centre Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="9"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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