Mice lacking phosphatase PP2A subunit PR61/B’δ (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β
Identifieur interne : 001A05 ( Pmc/Curation ); précédent : 001A04; suivant : 001A06Mice lacking phosphatase PP2A subunit PR61/B’δ (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β
Auteurs : Justin V. Louis [Belgique] ; Ellen Martens [Belgique] ; Peter Borghgraef [Belgique] ; Caroline Lambrecht [Belgique] ; Ward Sents [Belgique] ; Sari Longin [Belgique] ; Karen Zwaenepoel [Belgique] ; Robert Pijnenborg [Belgique] ; Isabelle Landrieu [France] ; Guy Lippens [France] ; Birgit Ledermann [Suisse] ; Jürgen Götz [Australie] ; Fred Van Leuven [Belgique] ; Jozef Goris [Belgique] ; Veerle Janssens [Belgique]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2011.
Abstract
Functional diversity of protein phosphatase 2A (PP2A) enzymes mainly results from their association with distinct regulatory subunits. To analyze the functions of one such holoenzyme in vivo, we generated mice lacking PR61/B’δ (B56δ), a subunit highly expressed in neural tissues. In PR61/B’δ-null mice the microtubule-associated protein tau becomes progressively phosphorylated at pathological epitopes in restricted brain areas, with marked immunoreactivity for the misfolded MC1-conformation but without neurofibrillary tangle formation. Behavioral tests indicated impaired sensorimotor but normal cognitive functions. These phenotypical characteristics were further underscored in PR61/B’δ-null mice mildly overexpressing human tau. PR61/B’δ-containing PP2A (PP2A
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DOI: 10.1073/pnas.1018777108
PubMed: 21482799
PubMed Central: 3084077
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mice lacking phosphatase PP2A subunit PR61/B’δ (<italic>Ppp2r5d</italic>) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β</title><author><name sortKey="Louis, Justin V" sort="Louis, Justin V" uniqKey="Louis J" first="Justin V." last="Louis">Justin V. Louis</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Martens, Ellen" sort="Martens, Ellen" uniqKey="Martens E" first="Ellen" last="Martens">Ellen Martens</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Borghgraef, Peter" sort="Borghgraef, Peter" uniqKey="Borghgraef P" first="Peter" last="Borghgraef">Peter Borghgraef</name><affiliation wicri:level="1"><nlm:aff id="aff2">Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Lambrecht, Caroline" sort="Lambrecht, Caroline" uniqKey="Lambrecht C" first="Caroline" last="Lambrecht">Caroline Lambrecht</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name 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Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Landrieu, Isabelle" sort="Landrieu, Isabelle" uniqKey="Landrieu I" first="Isabelle" last="Landrieu">Isabelle Landrieu</name><affiliation wicri:level="1"><nlm:aff id="aff4">Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8576, Unité de Glycobiologie Structurale et Fonctionelle–Institut Fédératif de Recherche 147, Université des Sciences et Technologies de Lille 1, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8576, Unité de Glycobiologie Structurale et Fonctionelle–Institut Fédératif de Recherche 147, Université des Sciences et Technologies de Lille 1</wicri:regionArea></affiliation></author><author><name sortKey="Lippens, Guy" sort="Lippens, Guy" uniqKey="Lippens G" first="Guy" last="Lippens">Guy Lippens</name><affiliation wicri:level="1"><nlm:aff id="aff4">Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8576, Unité de Glycobiologie Structurale et Fonctionelle–Institut Fédératif de Recherche 147, Université des Sciences et Technologies de Lille 1, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8576, Unité de Glycobiologie Structurale et Fonctionelle–Institut Fédératif de Recherche 147, Université des Sciences et Technologies de Lille 1</wicri:regionArea></affiliation></author><author><name sortKey="Ledermann, Birgit" sort="Ledermann, Birgit" uniqKey="Ledermann B" first="Birgit" last="Ledermann">Birgit Ledermann</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="aff5">Novartis Pharma AG, Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Novartis Pharma AG, Basel</wicri:regionArea></affiliation></author><author><name sortKey="Gotz, Jurgen" sort="Gotz, Jurgen" uniqKey="Gotz J" first="Jürgen" last="Götz">Jürgen Götz</name><affiliation wicri:level="1"><nlm:aff id="aff6">Alzheimer’s and Parkinson’s Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Camperdown, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Alzheimer’s and Parkinson’s Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Camperdown</wicri:regionArea></affiliation></author><author><name sortKey="Van Leuven, Fred" sort="Van Leuven, Fred" uniqKey="Van Leuven F" first="Fred" last="Van Leuven">Fred Van Leuven</name><affiliation wicri:level="1"><nlm:aff id="aff2">Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Goris, Jozef" sort="Goris, Jozef" uniqKey="Goris J" first="Jozef" last="Goris">Jozef Goris</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Janssens, Veerle" sort="Janssens, Veerle" uniqKey="Janssens V" first="Veerle" last="Janssens">Veerle Janssens</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, 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last="Louis">Justin V. Louis</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Martens, Ellen" sort="Martens, Ellen" uniqKey="Martens E" first="Ellen" last="Martens">Ellen Martens</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Borghgraef, Peter" sort="Borghgraef, Peter" uniqKey="Borghgraef P" first="Peter" last="Borghgraef">Peter Borghgraef</name><affiliation wicri:level="1"><nlm:aff id="aff2">Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Lambrecht, Caroline" sort="Lambrecht, Caroline" uniqKey="Lambrecht C" first="Caroline" last="Lambrecht">Caroline Lambrecht</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Sents, Ward" sort="Sents, Ward" uniqKey="Sents W" first="Ward" last="Sents">Ward Sents</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Longin, Sari" sort="Longin, Sari" uniqKey="Longin S" first="Sari" last="Longin">Sari Longin</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Zwaenepoel, Karen" sort="Zwaenepoel, Karen" uniqKey="Zwaenepoel K" first="Karen" last="Zwaenepoel">Karen Zwaenepoel</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Pijnenborg, Robert" sort="Pijnenborg, Robert" uniqKey="Pijnenborg R" first="Robert" last="Pijnenborg">Robert Pijnenborg</name><affiliation wicri:level="1"><nlm:aff id="aff3">Department of Gynaecology and Obstetrics, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Landrieu, Isabelle" sort="Landrieu, Isabelle" uniqKey="Landrieu I" first="Isabelle" last="Landrieu">Isabelle Landrieu</name><affiliation wicri:level="1"><nlm:aff id="aff4">Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8576, Unité de Glycobiologie Structurale et Fonctionelle–Institut Fédératif de Recherche 147, Université des Sciences et Technologies de Lille 1, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8576, Unité de Glycobiologie Structurale et Fonctionelle–Institut Fédératif de Recherche 147, Université des Sciences et Technologies de Lille 1</wicri:regionArea></affiliation></author><author><name sortKey="Lippens, Guy" sort="Lippens, Guy" uniqKey="Lippens G" first="Guy" last="Lippens">Guy Lippens</name><affiliation wicri:level="1"><nlm:aff id="aff4">Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8576, Unité de Glycobiologie Structurale et Fonctionelle–Institut Fédératif de Recherche 147, Université des Sciences et Technologies de Lille 1, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8576, Unité de Glycobiologie Structurale et Fonctionelle–Institut Fédératif de Recherche 147, Université des Sciences et Technologies de Lille 1</wicri:regionArea></affiliation></author><author><name sortKey="Ledermann, Birgit" sort="Ledermann, Birgit" uniqKey="Ledermann B" first="Birgit" last="Ledermann">Birgit Ledermann</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="aff5">Novartis Pharma AG, Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Novartis Pharma AG, Basel</wicri:regionArea></affiliation></author><author><name sortKey="Gotz, Jurgen" sort="Gotz, Jurgen" uniqKey="Gotz J" first="Jürgen" last="Götz">Jürgen Götz</name><affiliation wicri:level="1"><nlm:aff id="aff6">Alzheimer’s and Parkinson’s Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Camperdown, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Alzheimer’s and Parkinson’s Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Camperdown</wicri:regionArea></affiliation></author><author><name sortKey="Van Leuven, Fred" sort="Van Leuven, Fred" uniqKey="Van Leuven F" first="Fred" last="Van Leuven">Fred Van Leuven</name><affiliation wicri:level="1"><nlm:aff id="aff2">Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Goris, Jozef" sort="Goris, Jozef" uniqKey="Goris J" first="Jozef" last="Goris">Jozef Goris</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Janssens, Veerle" sort="Janssens, Veerle" uniqKey="Janssens V" first="Veerle" last="Janssens">Veerle Janssens</name><affiliation wicri:level="1"><nlm:aff id="aff1">Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven</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="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Functional diversity of protein phosphatase 2A (PP2A) enzymes mainly results from their association with distinct regulatory subunits. To analyze the functions of one such holoenzyme in vivo, we generated mice lacking PR61/B’δ (B56δ), a subunit highly expressed in neural tissues. In PR61/B’δ-null mice the microtubule-associated protein tau becomes progressively phosphorylated at pathological epitopes in restricted brain areas, with marked immunoreactivity for the misfolded MC1-conformation but without neurofibrillary tangle formation. Behavioral tests indicated impaired sensorimotor but normal cognitive functions. These phenotypical characteristics were further underscored in PR61/B’δ-null mice mildly overexpressing human tau. PR61/B’δ-containing PP2A (PP2A<sub><italic>T</italic>61<italic>δ</italic></sub>) poorly dephosphorylates tau in vitro, arguing against a direct dephosphorylation defect. Rather, the activity of glycogen synthase kinase-3β, a major tau kinase, was found increased, with decreased phosphorylation of Ser-9, a putative cyclin-dependent kinase 5 (CDK5) target. Accordingly, CDK5 activity is decreased, and its cellular activator p35, strikingly absent in the affected brain areas. As opposed to tau, p35 is an excellent PP2A<sub><italic>T</italic>61<italic>δ</italic></sub> substrate. Our data imply a nonredundant function for PR61/B’δ in phospho-tau homeostasis via an unexpected spatially restricted mechanism preventing p35 hyperphosphorylation and its subsequent degradation.</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="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">21482799</article-id><article-id pub-id-type="pmc">3084077</article-id><article-id pub-id-type="publisher-id">201018777</article-id><article-id pub-id-type="doi">10.1073/pnas.1018777108</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Biochemistry</subject></subj-group></subj-group></article-categories><title-group><article-title>Mice lacking phosphatase PP2A subunit PR61/B’δ (<italic>Ppp2r5d</italic>) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Louis</surname><given-names>Justin V.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="FN1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Martens</surname><given-names>Ellen</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="FN1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Borghgraef</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lambrecht</surname><given-names>Caroline</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sents</surname><given-names>Ward</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Longin</surname><given-names>Sari</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zwaenepoel</surname><given-names>Karen</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pijnenborg</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Landrieu</surname><given-names>Isabelle</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lippens</surname><given-names>Guy</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ledermann</surname><given-names>Birgit</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Götz</surname><given-names>Jürgen</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Van Leuven</surname><given-names>Fred</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Goris</surname><given-names>Jozef</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Janssens</surname><given-names>Veerle</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1"><label>a</label>Protein Phosphorylation and Proteomics Group, Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium;</aff><aff id="aff2"><label>b</label>Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit, Leuven, Belgium;</aff><aff id="aff3"><label>c</label>Department of Gynaecology and Obstetrics, Katholieke Universiteit, Leuven, Belgium;</aff><aff id="aff4"><label>d</label>Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8576, Unité de Glycobiologie Structurale et Fonctionelle–Institut Fédératif de Recherche 147, Université des Sciences et Technologies de Lille 1, France;</aff><aff id="aff5"><label>e</label>Novartis Pharma AG, Basel, Switzerland; and</aff><aff id="aff6"><label>f</label>Alzheimer’s and Parkinson’s Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Camperdown, Australia</aff></contrib-group><author-notes><corresp id="cor1"><sup>2</sup>To whom correspondence should be addressed. E-mail: <email>Veerle.janssens@med.kuleuven.be</email>.</corresp><fn fn-type="edited-by"><p>Edited by Thomas C. Südhof, Stanford University School of Medicine, Palo Alto, CA, and approved March 15, 2011 (received for review December 14, 2010)</p></fn><fn fn-type="participating-researchers"><p>Author contributions: J.V.L., E.M., F.V.L., J. Goris, and V.J. designed research; J.V.L., E.M., P.B., C.L., W.S., K.Z., R.P., and B.L. performed research; S.L., I.L., G.L., and J. Götz contributed new reagents/analytic tools; J.V.L., E.M., P.B., C.L., W.S., R.P., B.L., J. Götz, F.V.L., J. Goris, and V.J. analyzed data; and J.V.L., E.M., and V.J. wrote the paper.</p></fn><fn fn-type="equal" id="FN1"><p><sup>1</sup>J.V.L. and E.M. contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>26</day><month>4</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>11</day><month>4</month><year>2011</year></pub-date><volume>108</volume><issue>17</issue><fpage>6957</fpage><lpage>6962</lpage><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.1018777108.pdf"></self-uri><abstract><p>Functional diversity of protein phosphatase 2A (PP2A) enzymes mainly results from their association with distinct regulatory subunits. To analyze the functions of one such holoenzyme in vivo, we generated mice lacking PR61/B’δ (B56δ), a subunit highly expressed in neural tissues. In PR61/B’δ-null mice the microtubule-associated protein tau becomes progressively phosphorylated at pathological epitopes in restricted brain areas, with marked immunoreactivity for the misfolded MC1-conformation but without neurofibrillary tangle formation. Behavioral tests indicated impaired sensorimotor but normal cognitive functions. These phenotypical characteristics were further underscored in PR61/B’δ-null mice mildly overexpressing human tau. PR61/B’δ-containing PP2A (PP2A<sub><italic>T</italic>61<italic>δ</italic></sub>) poorly dephosphorylates tau in vitro, arguing against a direct dephosphorylation defect. Rather, the activity of glycogen synthase kinase-3β, a major tau kinase, was found increased, with decreased phosphorylation of Ser-9, a putative cyclin-dependent kinase 5 (CDK5) target. Accordingly, CDK5 activity is decreased, and its cellular activator p35, strikingly absent in the affected brain areas. As opposed to tau, p35 is an excellent PP2A<sub><italic>T</italic>61<italic>δ</italic></sub> substrate. Our data imply a nonredundant function for PR61/B’δ in phospho-tau homeostasis via an unexpected spatially restricted mechanism preventing p35 hyperphosphorylation and its subsequent degradation.</p></abstract><kwd-group><kwd>brain stem</kwd><kwd>knockout mouse</kwd><kwd>AT8</kwd><kwd>AT180</kwd><kwd>transgenic</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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