FAS-Dependent Cell Death in α-Synuclein Transgenic Oligodendrocyte Models of Multiple System Atrophy
Identifieur interne : 000D23 ( Main/Curation ); précédent : 000D22; suivant : 000D24FAS-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.
Url:
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><wicri:noRegion>Aarhus</wicri:noRegion></affiliation></author><author><name sortKey="Fillon, Gwenaelle" sort="Fillon, Gwenaelle" uniqKey="Fillon G" first="Gwenaëlle" last="Fillon">Gwenaëlle Fillon</name><affiliation wicri:level="4"><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><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université Louis-et-Maximilien de Munich</orgName></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><wicri:noRegion>New South Wales</wicri:noRegion></affiliation></author><author><name sortKey="Hansen, Hanne D" sort="Hansen, Hanne D" uniqKey="Hansen H" first="Hanne D." last="Hansen">Hanne D. 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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><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Pierre-et-Marie-Curie</orgName></affiliation></author><author><name sortKey="Lubetzki, Catherine" sort="Lubetzki, Catherine" uniqKey="Lubetzki C" first="Catherine" last="Lubetzki">Catherine Lubetzki</name><affiliation wicri:level="4"><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 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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><wicri:noRegion>Aarhus</wicri:noRegion></affiliation></author><author><name sortKey="Fillon, Gwenaelle" sort="Fillon, Gwenaelle" uniqKey="Fillon G" first="Gwenaëlle" last="Fillon">Gwenaëlle Fillon</name><affiliation wicri:level="4"><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><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université Louis-et-Maximilien de Munich</orgName></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><wicri:noRegion>New South Wales</wicri:noRegion></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="3"><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><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Neumann, Manuela" sort="Neumann, Manuela" uniqKey="Neumann M" first="Manuela" last="Neumann">Manuela Neumann</name><affiliation wicri:level="4"><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><placeName><settlement type="city">Zurich</settlement><region nuts="3" type="region">Canton de Zurich</region></placeName><orgName type="university">Université de Zurich</orgName></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><wicri:noRegion>Oldenburg</wicri:noRegion><wicri:noRegion>Oldenburg</wicri:noRegion><wicri:noRegion>Oldenburg</wicri:noRegion></affiliation></author><author><name sortKey="Haass, Christian" sort="Haass, Christian" uniqKey="Haass C" first="Christian" last="Haass">Christian Haass</name><affiliation wicri:level="4"><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><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université Louis-et-Maximilien de Munich</orgName></affiliation></author><author><name sortKey="Zalc, Bernard" sort="Zalc, Bernard" uniqKey="Zalc B" first="Bernard" last="Zalc">Bernard Zalc</name><affiliation wicri:level="4"><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><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Pierre-et-Marie-Curie</orgName></affiliation></author><author><name sortKey="Lubetzki, Catherine" sort="Lubetzki, Catherine" uniqKey="Lubetzki C" first="Catherine" last="Lubetzki">Catherine Lubetzki</name><affiliation wicri:level="4"><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><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Pierre-et-Marie-Curie</orgName></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><wicri:noRegion>South Australia</wicri:noRegion></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><wicri:noRegion>New South Wales</wicri:noRegion></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="3"><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><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="3"><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><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></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><wicri:noRegion>Aarhus</wicri:noRegion></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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