Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation
Identifieur interne : 000540 ( Pmc/Curation ); précédent : 000539; suivant : 000541Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation
Auteurs : Annemieke T. Van Der Goot ; Wentao Zhu [Allemagne] ; Rafael P. Vázquez-Manrique [France] ; Renée I. Seinstra ; Katja Dettmer [Allemagne] ; Helen Michels ; Francesca Farina [France] ; Jasper Krijnen [Pays-Bas] ; Ronald Melki [France] ; Rogier C. Buijsman [Pays-Bas] ; Mariana Ruiz Silva ; Karen L. Thijssen ; Ido P. Kema [Pays-Bas] ; Christian Neri [France] ; Peter J. Oefner [Allemagne] ; Ellen A. A. Nollen [Pays-Bas]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2012.
Abstract
Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer’s diseases. Here, we identify tryptophan 2,3-dioxygenase (
Url:
DOI: 10.1073/pnas.1203083109
PubMed: 22927396
PubMed Central: 3443121
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: Pour aller vers cette notice dans l'étape Curation :000543
Links to Exploration step
PMC:3443121Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation</title><author><name sortKey="Van Der Goot, Annemieke T" sort="Van Der Goot, Annemieke T" uniqKey="Van Der Goot A" first="Annemieke T." last="Van Der Goot">Annemieke T. Van Der Goot</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Zhu, Wentao" sort="Zhu, Wentao" uniqKey="Zhu W" first="Wentao" last="Zhu">Wentao Zhu</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Functional Genomics,<institution>University of Regensburg</institution>, 93053 Regensburg,<country>Germany</country>;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Vazquez Manrique, Rafael P" sort="Vazquez Manrique, Rafael P" uniqKey="Vazquez Manrique R" first="Rafael P." last="Vázquez-Manrique">Rafael P. Vázquez-Manrique</name><affiliation wicri:level="1"><nlm:aff id="aff4">Institut National de la Santé et de la Recherche Médicale, Unit 894,<institution>Laboratory of Neuronal Cell Biology and Pathology</institution>, 75014 Paris,<country>France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Seinstra, Renee I" sort="Seinstra, Renee I" uniqKey="Seinstra R" first="Renée I." last="Seinstra">Renée I. Seinstra</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Dettmer, Katja" sort="Dettmer, Katja" uniqKey="Dettmer K" first="Katja" last="Dettmer">Katja Dettmer</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Functional Genomics,<institution>University of Regensburg</institution>, 93053 Regensburg,<country>Germany</country>;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Michels, Helen" sort="Michels, Helen" uniqKey="Michels H" first="Helen" last="Michels">Helen Michels</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Farina, Francesca" sort="Farina, Francesca" uniqKey="Farina F" first="Francesca" last="Farina">Francesca Farina</name><affiliation wicri:level="1"><nlm:aff id="aff4">Institut National de la Santé et de la Recherche Médicale, Unit 894,<institution>Laboratory of Neuronal Cell Biology and Pathology</institution>, 75014 Paris,<country>France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Krijnen, Jasper" sort="Krijnen, Jasper" uniqKey="Krijnen J" first="Jasper" last="Krijnen">Jasper Krijnen</name><affiliation wicri:level="1"><nlm:aff id="aff2">Laboratory Medicine, University of Groningen,<institution>University Medical Centre Groningen</institution>, 9700 RB, Groningen,<country>The Netherlands</country>;</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name><affiliation wicri:level="1"><nlm:aff id="aff5">Laboratoire d’Enzymologie et Biochimie Structurales,<institution>Centre National de la Recherche Scientifique</institution>,<country>91190 Gif-sur-Yvette, France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea></wicri:regionArea></affiliation></author><author><name sortKey="Buijsman, Rogier C" sort="Buijsman, Rogier C" uniqKey="Buijsman R" first="Rogier C." last="Buijsman">Rogier C. Buijsman</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="aff6"><institution>Translational Research Centre B.V.</institution>, 5342 AC, Oss,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ruiz Silva, Mariana" sort="Ruiz Silva, Mariana" uniqKey="Ruiz Silva M" first="Mariana" last="Ruiz Silva">Mariana Ruiz Silva</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Thijssen, Karen L" sort="Thijssen, Karen L" uniqKey="Thijssen K" first="Karen L." last="Thijssen">Karen L. Thijssen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Kema, Ido P" sort="Kema, Ido P" uniqKey="Kema I" first="Ido P." last="Kema">Ido P. Kema</name><affiliation wicri:level="1"><nlm:aff id="aff2">Laboratory Medicine, University of Groningen,<institution>University Medical Centre Groningen</institution>, 9700 RB, Groningen,<country>The Netherlands</country>;</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Neri, Christian" sort="Neri, Christian" uniqKey="Neri C" first="Christian" last="Neri">Christian Neri</name><affiliation wicri:level="1"><nlm:aff id="aff4">Institut National de la Santé et de la Recherche Médicale, Unit 894,<institution>Laboratory of Neuronal Cell Biology and Pathology</institution>, 75014 Paris,<country>France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Oefner, Peter J" sort="Oefner, Peter J" uniqKey="Oefner P" first="Peter J." last="Oefner">Peter J. Oefner</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Functional Genomics,<institution>University of Regensburg</institution>, 93053 Regensburg,<country>Germany</country>;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nollen, Ellen A A" sort="Nollen, Ellen A A" uniqKey="Nollen E" first="Ellen A. A." last="Nollen">Ellen A. A. Nollen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7">University of Groningen, University Medical Centre Groningen,<institution>European Research Institute for the Biology of Aging</institution>,<country>9700 AD, Groningen, The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea></wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22927396</idno><idno type="pmc">3443121</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443121</idno><idno type="RBID">PMC:3443121</idno><idno type="doi">10.1073/pnas.1203083109</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">000543</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000543</idno><idno type="wicri:Area/Pmc/Curation">000540</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000540</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation</title><author><name sortKey="Van Der Goot, Annemieke T" sort="Van Der Goot, Annemieke T" uniqKey="Van Der Goot A" first="Annemieke T." last="Van Der Goot">Annemieke T. Van Der Goot</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Zhu, Wentao" sort="Zhu, Wentao" uniqKey="Zhu W" first="Wentao" last="Zhu">Wentao Zhu</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Functional Genomics,<institution>University of Regensburg</institution>, 93053 Regensburg,<country>Germany</country>;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Vazquez Manrique, Rafael P" sort="Vazquez Manrique, Rafael P" uniqKey="Vazquez Manrique R" first="Rafael P." last="Vázquez-Manrique">Rafael P. Vázquez-Manrique</name><affiliation wicri:level="1"><nlm:aff id="aff4">Institut National de la Santé et de la Recherche Médicale, Unit 894,<institution>Laboratory of Neuronal Cell Biology and Pathology</institution>, 75014 Paris,<country>France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Seinstra, Renee I" sort="Seinstra, Renee I" uniqKey="Seinstra R" first="Renée I." last="Seinstra">Renée I. Seinstra</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Dettmer, Katja" sort="Dettmer, Katja" uniqKey="Dettmer K" first="Katja" last="Dettmer">Katja Dettmer</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Functional Genomics,<institution>University of Regensburg</institution>, 93053 Regensburg,<country>Germany</country>;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Michels, Helen" sort="Michels, Helen" uniqKey="Michels H" first="Helen" last="Michels">Helen Michels</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Farina, Francesca" sort="Farina, Francesca" uniqKey="Farina F" first="Francesca" last="Farina">Francesca Farina</name><affiliation wicri:level="1"><nlm:aff id="aff4">Institut National de la Santé et de la Recherche Médicale, Unit 894,<institution>Laboratory of Neuronal Cell Biology and Pathology</institution>, 75014 Paris,<country>France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Krijnen, Jasper" sort="Krijnen, Jasper" uniqKey="Krijnen J" first="Jasper" last="Krijnen">Jasper Krijnen</name><affiliation wicri:level="1"><nlm:aff id="aff2">Laboratory Medicine, University of Groningen,<institution>University Medical Centre Groningen</institution>, 9700 RB, Groningen,<country>The Netherlands</country>;</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name><affiliation wicri:level="1"><nlm:aff id="aff5">Laboratoire d’Enzymologie et Biochimie Structurales,<institution>Centre National de la Recherche Scientifique</institution>,<country>91190 Gif-sur-Yvette, France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea></wicri:regionArea></affiliation></author><author><name sortKey="Buijsman, Rogier C" sort="Buijsman, Rogier C" uniqKey="Buijsman R" first="Rogier C." last="Buijsman">Rogier C. Buijsman</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="aff6"><institution>Translational Research Centre B.V.</institution>, 5342 AC, Oss,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ruiz Silva, Mariana" sort="Ruiz Silva, Mariana" uniqKey="Ruiz Silva M" first="Mariana" last="Ruiz Silva">Mariana Ruiz Silva</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Thijssen, Karen L" sort="Thijssen, Karen L" uniqKey="Thijssen K" first="Karen L." last="Thijssen">Karen L. Thijssen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Kema, Ido P" sort="Kema, Ido P" uniqKey="Kema I" first="Ido P." last="Kema">Ido P. Kema</name><affiliation wicri:level="1"><nlm:aff id="aff2">Laboratory Medicine, University of Groningen,<institution>University Medical Centre Groningen</institution>, 9700 RB, Groningen,<country>The Netherlands</country>;</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Neri, Christian" sort="Neri, Christian" uniqKey="Neri C" first="Christian" last="Neri">Christian Neri</name><affiliation wicri:level="1"><nlm:aff id="aff4">Institut National de la Santé et de la Recherche Médicale, Unit 894,<institution>Laboratory of Neuronal Cell Biology and Pathology</institution>, 75014 Paris,<country>France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Oefner, Peter J" sort="Oefner, Peter J" uniqKey="Oefner P" first="Peter J." last="Oefner">Peter J. Oefner</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Functional Genomics,<institution>University of Regensburg</institution>, 93053 Regensburg,<country>Germany</country>;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nollen, Ellen A A" sort="Nollen, Ellen A A" uniqKey="Nollen E" first="Ellen A. A." last="Nollen">Ellen A. A. Nollen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7">University of Groningen, University Medical Centre Groningen,<institution>European Research Institute for the Biology of Aging</institution>,<country>9700 AD, Groningen, The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea></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="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer’s diseases. Here, we identify tryptophan 2,3-dioxygenase (<italic>tdo-2</italic>), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity in a <italic>Caenorhabditis elegans</italic> model. Depletion of <italic>tdo-2</italic> also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that <italic>tdo-2</italic> functions as a general regulator of protein homeostasis. Analysis of metabolite levels in <italic>C. elegans</italic> strains with mutations in enzymes that act downstream of <italic>tdo-2</italic> indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of <italic>tdo-2</italic> increases tryptophan levels, and feeding worms with extra <sc>l</sc>-tryptophan also suppresses toxicity, suggesting that <italic>tdo-2</italic> regulates proteotoxicity through tryptophan. Depletion of <italic>tdo-2</italic> extends lifespan in these worms. Together, these results implicate <italic>tdo-2</italic> as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases.</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">22927396</article-id><article-id pub-id-type="pmc">3443121</article-id><article-id pub-id-type="publisher-id">201203083</article-id><article-id pub-id-type="doi">10.1073/pnas.1203083109</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Cell Biology</subject></subj-group></subj-group></article-categories><title-group><article-title>Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation</article-title><alt-title alt-title-type="short">TDO-2 regulates age-related proteotoxicity</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>van der Goot</surname><given-names>Annemieke T.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhu</surname><given-names>Wentao</given-names></name><xref ref-type="aff" rid="aff3"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vázquez-Manrique</surname><given-names>Rafael P.</given-names></name><xref ref-type="aff" rid="aff4"><sup>c</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Seinstra</surname><given-names>Renée I.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dettmer</surname><given-names>Katja</given-names></name><xref ref-type="aff" rid="aff3"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Michels</surname><given-names>Helen</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Farina</surname><given-names>Francesca</given-names></name><xref ref-type="aff" rid="aff4"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Krijnen</surname><given-names>Jasper</given-names></name><xref ref-type="aff" rid="aff2"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Melki</surname><given-names>Ronald</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Buijsman</surname><given-names>Rogier C.</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ruiz Silva</surname><given-names>Mariana</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Thijssen</surname><given-names>Karen L.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kema</surname><given-names>Ido P.</given-names></name><xref ref-type="aff" rid="aff2"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Neri</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="aff4"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Oefner</surname><given-names>Peter J.</given-names></name><xref ref-type="aff" rid="aff3"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nollen</surname><given-names>Ellen A. A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff7"><sup>g</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1">Departments of<sup>a</sup>Genetics and</aff><aff id="aff2"><sup>d</sup>Laboratory Medicine, University of Groningen,<institution>University Medical Centre Groningen</institution>, 9700 RB, Groningen,<country>The Netherlands</country>;</aff><aff id="aff3"><sup>b</sup>Institute of Functional Genomics,<institution>University of Regensburg</institution>, 93053 Regensburg,<country>Germany</country>;</aff><aff id="aff4"><sup>c</sup>Institut National de la Santé et de la Recherche Médicale, Unit 894,<institution>Laboratory of Neuronal Cell Biology and Pathology</institution>, 75014 Paris,<country>France</country>;</aff><aff id="aff5"><sup>e</sup>Laboratoire d’Enzymologie et Biochimie Structurales,<institution>Centre National de la Recherche Scientifique</institution>,<country>91190 Gif-sur-Yvette, France</country>;</aff><aff id="aff6"><sup>f</sup><institution>Translational Research Centre B.V.</institution>, 5342 AC, Oss,<country>The Netherlands</country>; and</aff><aff id="aff7"><sup>g</sup>University of Groningen, University Medical Centre Groningen,<institution>European Research Institute for the Biology of Aging</institution>,<country>9700 AD, Groningen, The Netherlands</country></aff></contrib-group><author-notes><corresp id="cor1"><sup>2</sup>To whom correspondence should be addressed. E-mail: <email>e.a.a.nollen@umcg.nl</email>.</corresp><fn fn-type="edited-by"><p>Edited by F. Ulrich Hartl, Max Planck Institute of Biochemistry, Martinsried, Germany, and approved July 20, 2012 (received for review February 26, 2012)</p></fn><fn fn-type="con"><p>Author contributions: A.T.v.d.G. and E.A.A.N. designed research; A.T.v.d.G., W.Z., R.P.V.-M., R.I.S., K.D., H.M., F.F., J.K., R.M., M.R.S., and K.L.T. performed research; R.C.B., I.P.K., and P.J.O. contributed new reagents/analytic tools; A.T.v.d.G., W.Z., R.P.V.-M., I.P.K., C.N., P.J.O., and E.A.A.N. analyzed data; and A.T.v.d.G. and E.A.A.N. wrote the paper.</p></fn><fn id="fn1" fn-type="present-address"><p><sup>1</sup>Present address: Grupo de Investigación en Enfermedades Neurosensoriales, Instituto de Investigación Sanitaria IIS-La Fe, 46009 Valencia, Spain.</p></fn></author-notes><pub-date pub-type="ppub"><day>11</day><month>9</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>27</day><month>8</month><year>2012</year></pub-date><pub-date pub-type="pmc-release"><day>27</day><month>8</month><year>2012</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>109</volume><issue>37</issue><fpage>14912</fpage><lpage>14917</lpage><permissions><license license-type="open-access"><license-p>Freely available online through the PNAS open access option.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.201203083.pdf"></self-uri><abstract><p>Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer’s diseases. Here, we identify tryptophan 2,3-dioxygenase (<italic>tdo-2</italic>), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity in a <italic>Caenorhabditis elegans</italic> model. Depletion of <italic>tdo-2</italic> also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that <italic>tdo-2</italic> functions as a general regulator of protein homeostasis. Analysis of metabolite levels in <italic>C. elegans</italic> strains with mutations in enzymes that act downstream of <italic>tdo-2</italic> indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of <italic>tdo-2</italic> increases tryptophan levels, and feeding worms with extra <sc>l</sc>-tryptophan also suppresses toxicity, suggesting that <italic>tdo-2</italic> regulates proteotoxicity through tryptophan. Depletion of <italic>tdo-2</italic> extends lifespan in these worms. Together, these results implicate <italic>tdo-2</italic> as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases.</p></abstract><kwd-group><kwd>Huntington</kwd><kwd>longevity</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonFranceV1/Data/Pmc/Curation
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000540 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd -nk 000540 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= ParkinsonFranceV1
|flux= Pmc
|étape= Curation
|type= RBID
|clé= PMC:3443121
|texte= Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Curation/RBID.i -Sk "pubmed:22927396" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd \
| NlmPubMed2Wicri -a ParkinsonFranceV1
| This area was generated with Dilib version V0.6.29. |  |