C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice
Identifieur interne : 000542 ( Pmc/Curation ); précédent : 000541; suivant : 000543C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice
Auteurs : Christian S. Lobsiger [États-Unis, France] ; Severine Boillée [États-Unis, France] ; Christine Pozniak [États-Unis] ; Amir M. Khan [États-Unis] ; Melissa Mcalonis-Downes [États-Unis] ; Joseph W. Lewcock [États-Unis] ; Don W. Cleveland [États-Unis]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2013.
Abstract
Activation of the immune system within the nervous system is widely found in neurodegenerative diseases, including ALS. In mice that develop fatal paralytic disease from ALS-causing superoxide dismutase (SOD1) mutants, motor neurons activate expression of C1q, the initiating component of the classic complement system. As C1q and complement play a central role in developmental synapse elimination, disease-linked activation has suggested that it drives motor neuron denervation. Instead, suppressing C1q induction by gene deletion is shown to enhance loss, not retention, of synapses, whereas elimination of global complement activation by C1q or C3 gene deletions leave onset and progression of paralytic disease unaffected. Thus, C1q induction and complement activation are not significant contributors to SOD1 mutant-mediated ALS disease mechanism in mice.
Url:
DOI: 10.1073/pnas.1318309110
PubMed: 24170856
PubMed Central: 3831990
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Lobsiger</name><affiliation wicri:level="2"><nlm:aff id="aff1">Ludwig Institute for Cancer Research, Department of Medicine and Neuroscience,<institution>University of California, San Diego</institution>, La Jolla, CA 92093;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>, La Jolla</wicri:cityArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Institut National de la Santé et de la Recherche Medicale (INSERM), Unité Mixte de Recherche U975, Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Medicale (INSERM), Unité Mixte de Recherche U975, Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Centre National de la Recherche Scientifique (CNRS), Unite Mixte de Recherche 7225, 75013 Paris, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique (CNRS), Unite Mixte de Recherche 7225, 75013 Paris</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4">Université Pierre et Marie Curie, Sorbonne Universités, 75005 Paris, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université Pierre et Marie Curie, Sorbonne Universités, 75005 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Boillee, Severine" sort="Boillee, Severine" uniqKey="Boillee S" first="Severine" last="Boillée">Severine Boillée</name><affiliation wicri:level="2"><nlm:aff id="aff1">Ludwig Institute for Cancer Research, Department of Medicine and Neuroscience,<institution>University of California, San Diego</institution>, La Jolla, CA 92093;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>, La Jolla</wicri:cityArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Institut National de la Santé et de la Recherche Medicale (INSERM), Unité Mixte de Recherche U975, Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Medicale (INSERM), Unité Mixte de Recherche U975, Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Centre National de la Recherche Scientifique (CNRS), Unite Mixte de Recherche 7225, 75013 Paris, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique (CNRS), Unite Mixte de Recherche 7225, 75013 Paris</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4">Université Pierre et Marie Curie, Sorbonne Universités, 75005 Paris, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université Pierre et Marie Curie, Sorbonne Universités, 75005 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Pozniak, Christine" sort="Pozniak, Christine" uniqKey="Pozniak C" first="Christine" last="Pozniak">Christine Pozniak</name><affiliation wicri:level="2"><nlm:aff id="aff5">Neurodegeneration Laboratories, Department of Neuroscience,<institution>Genentech</institution>, South San Francisco, CA 94080</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>, South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Khan, Amir M" sort="Khan, Amir M" uniqKey="Khan A" first="Amir M." last="Khan">Amir M. Khan</name><affiliation wicri:level="2"><nlm:aff id="aff1">Ludwig Institute for Cancer Research, Department of Medicine and Neuroscience,<institution>University of California, San Diego</institution>, La Jolla, CA 92093;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>, La Jolla</wicri:cityArea></affiliation></author><author><name sortKey="Mcalonis Downes, Melissa" sort="Mcalonis Downes, Melissa" uniqKey="Mcalonis Downes M" first="Melissa" last="Mcalonis-Downes">Melissa Mcalonis-Downes</name><affiliation wicri:level="2"><nlm:aff id="aff1">Ludwig Institute for Cancer Research, Department of Medicine and Neuroscience,<institution>University of California, San Diego</institution>, La Jolla, CA 92093;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>, La Jolla</wicri:cityArea></affiliation></author><author><name sortKey="Lewcock, Joseph W" sort="Lewcock, Joseph W" uniqKey="Lewcock J" first="Joseph W." last="Lewcock">Joseph W. Lewcock</name><affiliation wicri:level="2"><nlm:aff id="aff5">Neurodegeneration Laboratories, Department of Neuroscience,<institution>Genentech</institution>, South San Francisco, CA 94080</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>, South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Cleveland, Don W" sort="Cleveland, Don W" uniqKey="Cleveland D" first="Don W." last="Cleveland">Don W. Cleveland</name><affiliation wicri:level="2"><nlm:aff id="aff1">Ludwig Institute for Cancer Research, Department of Medicine and Neuroscience,<institution>University of California, San Diego</institution>, La Jolla, CA 92093;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>, La Jolla</wicri:cityArea></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="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>Activation of the immune system within the nervous system is widely found in neurodegenerative diseases, including ALS. In mice that develop fatal paralytic disease from ALS-causing superoxide dismutase (SOD1) mutants, motor neurons activate expression of C1q, the initiating component of the classic complement system. As C1q and complement play a central role in developmental synapse elimination, disease-linked activation has suggested that it drives motor neuron denervation. Instead, suppressing C1q induction by gene deletion is shown to enhance loss, not retention, of synapses, whereas elimination of global complement activation by C1q or C3 gene deletions leave onset and progression of paralytic disease unaffected. Thus, C1q induction and complement activation are not significant contributors to SOD1 mutant-mediated ALS disease mechanism in mice.</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="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><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">24170856</article-id><article-id pub-id-type="pmc">3831990</article-id><article-id pub-id-type="publisher-id">201318309</article-id><article-id pub-id-type="doi">10.1073/pnas.1318309110</article-id><article-categories><subj-group subj-group-type="heading"><subject>PNAS Plus</subject></subj-group><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Neuroscience</subject></subj-group></subj-group><series-title>PNAS Plus</series-title></article-categories><title-group><article-title>C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice</article-title><alt-title alt-title-type="short">Role of C1q and complement in ALS mice</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lobsiger</surname><given-names>Christian S.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref><xref ref-type="aff" rid="aff4"><sup>d</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref><xref ref-type="author-notes" rid="fn2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Boillée</surname><given-names>Severine</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref><xref ref-type="aff" rid="aff4"><sup>d</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref><xref ref-type="author-notes" rid="fn2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pozniak</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Khan</surname><given-names>Amir M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn3"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>McAlonis-Downes</surname><given-names>Melissa</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lewcock</surname><given-names>Joseph W.</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cleveland</surname><given-names>Don W.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>3</sup></xref></contrib><aff id="aff1"><sup>a</sup>Ludwig Institute for Cancer Research, Department of Medicine and Neuroscience,<institution>University of California, San Diego</institution>, La Jolla, CA 92093;</aff><aff id="aff2"><sup>b</sup>Institut National de la Santé et de la Recherche Medicale (INSERM), Unité Mixte de Recherche U975, Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris, France;</aff><aff id="aff3"><sup>c</sup>Centre National de la Recherche Scientifique (CNRS), Unite Mixte de Recherche 7225, 75013 Paris, France;</aff><aff id="aff4"><sup>d</sup>Université Pierre et Marie Curie, Sorbonne Universités, 75005 Paris, France;</aff><aff id="aff5"><sup>e</sup>Neurodegeneration Laboratories, Department of Neuroscience,<institution>Genentech</institution>, South San Francisco, CA 94080</aff></contrib-group><author-notes><corresp id="cor1"><sup>3</sup>To whom correspondence may be addressed. E-mail: <email>christian.lobsiger@upmc.fr</email> or <email>dcleveland@ucsd.edu</email>.</corresp><fn fn-type="edited-by"><p>Contributed by Don W. Cleveland, October 5, 2013 (sent for review February 17, 2013)</p></fn><fn fn-type="con"><p>Author contributions: C.S.L., S.B., J.W.L., and D.W.C. designed research; C.S.L., S.B., C.P., A.M.K., and M.M.-D. performed research; C.S.L., S.B., C.P., A.M.K., and M.M.-D. analyzed data; and C.S.L., S.B., J.W.L., and D.W.C. wrote the paper.</p></fn><fn fn-type="equal" id="fn1"><p><sup>1</sup>C.S.L. and S.B. contributed equally to this work.</p></fn><fn fn-type="present-address" id="fn2"><p><sup>2</sup>Present address: Institut National de la Santé et de la Recherche Medicale (INSERM), Unité Mixte de Recherche U975, Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris, France.</p></fn><fn fn-type="present-address" id="fn3"><p><sup>4</sup>Present address: The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064.</p></fn></author-notes><pub-date pub-type="ppub"><day>12</day><month>11</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>29</day><month>10</month><year>2013</year></pub-date><volume>110</volume><issue>46</issue><fpage>E4385</fpage><lpage>E4392</lpage><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.201318309.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>Activation of the immune system within the nervous system is widely found in neurodegenerative diseases, including ALS. In mice that develop fatal paralytic disease from ALS-causing superoxide dismutase (SOD1) mutants, motor neurons activate expression of C1q, the initiating component of the classic complement system. As C1q and complement play a central role in developmental synapse elimination, disease-linked activation has suggested that it drives motor neuron denervation. Instead, suppressing C1q induction by gene deletion is shown to enhance loss, not retention, of synapses, whereas elimination of global complement activation by C1q or C3 gene deletions leave onset and progression of paralytic disease unaffected. Thus, C1q induction and complement activation are not significant contributors to SOD1 mutant-mediated ALS disease mechanism in mice.</p></abstract><abstract><p>Accumulating evidence from mice expressing ALS-causing mutations in superoxide dismutase (SOD1) has implicated pathological immune responses in motor neuron degeneration. This includes microglial activation, lymphocyte infiltration, and the induction of C1q, the initiating component of the classic complement system that is the protein-based arm of the innate immune response, in motor neurons of multiple ALS mouse models expressing dismutase active or inactive SOD1 mutants. Robust induction early in disease course is now identified for multiple complement components (including <italic>C1q</italic>, <italic>C4</italic>, and <italic>C3</italic>) in spinal cords of SOD1 mutant-expressing mice, consistent with initial intraneuronal C1q induction, followed by global activation of the complement pathway. We now test if this activation is a mechanistic contributor to disease. Deletion of the <italic>C1q</italic> gene in mice expressing an ALS-causing mutant in SOD1 to eliminate C1q induction, and complement cascade activation that follows from it, is demonstrated to produce changes in microglial morphology accompanied by enhanced loss, not retention, of synaptic densities during disease. C1q-dependent synaptic loss is shown to be especially prominent for cholinergic C-bouton nerve terminal input onto motor neurons in affected C1q-deleted SOD1 mutant mice. Nevertheless, overall onset and progression of disease are unaffected in C1q- and C3-deleted ALS mice, thus establishing that C1q induction and classic or alternative complement pathway activation do not contribute significantly to SOD1 mutant-mediated ALS pathogenesis in mice.</p></abstract><kwd-group><kwd>amyotrophic lateral sclerosis</kwd><kwd>motoneuron</kwd><kwd>synaptic density</kwd><kwd>gender differences</kwd><kwd>neuroinflammation</kwd></kwd-group><counts><page-count count="8"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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