Cellular factors controlling mutant huntingtin aggregation
Identifieur interne : 000154 ( Hal/Corpus ); précédent : 000153; suivant : 000155Cellular factors controlling mutant huntingtin aggregation
Auteurs : Erwann RousseauSource :
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Abstract
Aggregates deposition in neurons of patients is a generic feature of neurodegenerative diseases like Huntington's disease, Parkinson and Alzheimer's diseases. The mechanism of aggregates formation is unknown. The aim of this thesis is to study the mechanism of polyglutamine proteins aggregation. We have discovered that cellular environment plays a central role in the polyglutamine protein aggregation mechanism (Rousseau et al., 2004). This suggested that some factors modulate polyglutamine protein aggregation in cells. Looking for these factors, we found that two subunits of the 19S proteasome, Rpt6 and Rpt4 enhance the aggregation of the Huntingtin protein in cells. Down regulation of Rpt6 by siRNA decreases Huntingtin inclusion formation. When targeted to the proteasome by a ubiquitin independent pathway mutant Huntingtin is efficiently degraded. Aggregation of mutant Huntingtin protein is not a consequence of a proteasome proteolytic failure but is elicited when unfolding by the chaperone subunits of the 19S particle is uncoupled from proteolysis by the 20S proteasome. This work highlights the key role for cellular environment and particularly 19S proteasome in the control of polyglutamine protein aggregation.
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The mechanism of aggregates formation is unknown. The aim of this thesis is to study the mechanism of polyglutamine proteins aggregation. We have discovered that cellular environment plays a central role in the polyglutamine protein aggregation mechanism (Rousseau et al., 2004). This suggested that some factors modulate polyglutamine protein aggregation in cells. Looking for these factors, we found that two subunits of the 19S proteasome, Rpt6 and Rpt4 enhance the aggregation of the Huntingtin protein in cells. Down regulation of Rpt6 by siRNA decreases Huntingtin inclusion formation. When targeted to the proteasome by a ubiquitin independent pathway mutant Huntingtin is efficiently degraded. Aggregation of mutant Huntingtin protein is not a consequence of a proteasome proteolytic failure but is elicited when unfolding by the chaperone subunits of the 19S particle is uncoupled from proteolysis by the 20S proteasome. This work highlights the key role for cellular environment and particularly 19S proteasome in the control of polyglutamine protein aggregation.</div></front></TEI><hal api="V3"><titleStmt><title xml:lang="en">Cellular factors controlling mutant huntingtin aggregation</title><title xml:lang="fr">Facteurs cellulaires contrôlant l'agrégation des protéines à expansion de polyglutamine</title><author role="aut"><persName><forename type="first">Erwann</forename><surname>Rousseau</surname></persName><idno type="halauthorid">233584</idno><affiliation ref="#struct-1309"></affiliation></author><editor role="depositor"><persName><forename>Theses</forename><surname>Bupmc</surname></persName><email type="md5">ce30a2c4c7b98017ea1c47c186c22e91</email><email type="domain">upmc.fr</email></editor></titleStmt><editionStmt><edition n="v1" type="current"><date type="whenSubmitted">2013-04-10 10:52:29</date><date type="whenModified">2016-09-28 15:42:35</date><date type="whenReleased">2013-04-10 10:58:49</date><date type="whenProduced">2007-11-23</date><date type="whenEndEmbargoed">2013-04-10</date><ref type="file" target="https://tel.archives-ouvertes.fr/tel-00810962/document"><date notBefore="2013-04-10"></date></ref><ref type="file" n="1" target="https://tel.archives-ouvertes.fr/tel-00810962/file/ThA_se_Erwann_Rousseau_PDF.pdf"><date notBefore="2013-04-10"></date></ref></edition><respStmt><resp>contributor</resp><name key="181669"><persName><forename>Theses</forename><surname>Bupmc</surname></persName><email type="md5">ce30a2c4c7b98017ea1c47c186c22e91</email><email type="domain">upmc.fr</email></name></respStmt></editionStmt><publicationStmt><distributor>CCSD</distributor><idno type="halId">tel-00810962</idno><idno type="halUri">https://tel.archives-ouvertes.fr/tel-00810962</idno><idno type="halBibtex">rousseau:tel-00810962</idno><idno type="halRefHtml">Biochimie, Biologie Moléculaire. Université Pierre et Marie Curie - Paris VI, 2007. Français. <NNT : 2007PA066375></idno><idno type="halRef">Biochimie, Biologie Moléculaire. Université Pierre et Marie Curie - Paris VI, 2007. Français. <NNT : 2007PA066375></idno></publicationStmt><seriesStmt><idno type="stamp" n="CNRS">CNRS - Centre national de la recherche scientifique</idno><idno type="stamp" n="THESES-UPMC">Thèses de l'Université Pierre et Marie Curie</idno><idno type="stamp" n="ENS-PARIS">Ecole Normale Supérieure de Paris</idno><idno type="stamp" n="PSL">Paris Sciences et Lettres (PSL) Research University</idno></seriesStmt><notesStmt></notesStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Cellular factors controlling mutant huntingtin aggregation</title><title xml:lang="fr">Facteurs cellulaires contrôlant l'agrégation des protéines à expansion de polyglutamine</title><author role="aut"><persName><forename type="first">Erwann</forename><surname>Rousseau</surname></persName><idno type="halauthorid">233584</idno><affiliation ref="#struct-1309"></affiliation></author></analytic><monogr><idno type="nnt">2007PA066375</idno><imprint><date type="dateDefended">2007-11-23</date></imprint><authority type="institution">Université Pierre et Marie Curie - Paris VI</authority><authority type="school">InterBio</authority><authority type="supervisor">Anne Bertolotti</authority><authority type="jury">Philippe Denoulet Président</authority><authority type="jury">Philippe Djian Rapporteur</authority><authority type="jury">Olivier Coux Rapporteur</authority><authority type="jury">Bertrand Friguet Examinateur</authority><authority type="jury">Anne Bertolotti Directeur de thèse</authority></monogr></biblStruct></sourceDesc><profileDesc><langUsage><language ident="fr">French</language></langUsage><textClass><keywords scheme="author"><term xml:lang="fr">agrégation</term><term xml:lang="fr">polyglutamine</term><term xml:lang="fr">chaperon</term><term xml:lang="fr">protéasome</term><term xml:lang="fr">ubiquitine</term><term xml:lang="it">aggregation</term><term xml:lang="it">chaperone</term><term xml:lang="it">ubiquitin</term></keywords><classCode scheme="halDomain" n="sdv.bbm">Life Sciences [q-bio]/Biochemistry, Molecular Biology</classCode><classCode scheme="halTypology" n="THESE">Theses</classCode></textClass><abstract xml:lang="en">Aggregates deposition in neurons of patients is a generic feature of neurodegenerative diseases like Huntington's disease, Parkinson and Alzheimer's diseases. The mechanism of aggregates formation is unknown. The aim of this thesis is to study the mechanism of polyglutamine proteins aggregation. We have discovered that cellular environment plays a central role in the polyglutamine protein aggregation mechanism (Rousseau et al., 2004). This suggested that some factors modulate polyglutamine protein aggregation in cells. Looking for these factors, we found that two subunits of the 19S proteasome, Rpt6 and Rpt4 enhance the aggregation of the Huntingtin protein in cells. Down regulation of Rpt6 by siRNA decreases Huntingtin inclusion formation. When targeted to the proteasome by a ubiquitin independent pathway mutant Huntingtin is efficiently degraded. Aggregation of mutant Huntingtin protein is not a consequence of a proteasome proteolytic failure but is elicited when unfolding by the chaperone subunits of the 19S particle is uncoupled from proteolysis by the 20S proteasome. This work highlights the key role for cellular environment and particularly 19S proteasome in the control of polyglutamine protein aggregation.</abstract><abstract xml:lang="fr">Les maladies neurodégénératives telles que les maladies de Huntington, de Parkinson et d'Alzheimer ont la caractéristique commune de présenter des agrégats de protéines spécifiques dans les neurones des patients atteints par ces pathologies. Le mécanisme par lequel ces structures se forment est encore inconnu. L'objectif de ce travail a consisté en l'étude du mécanisme d'agrégation des protéines à expansion de polyglutamine. Nous avons découvert que l'environnement cellulaire joue un rôle critique dans la capacité à s'agréger des protéines à expansion de polyglutamine (Rousseau et al., 2004). Ce travail suggère l'existence de modulateurs de l'agrégation des protéines à expansion de polyglutamine. En cherchant des modulateurs d'agrégation nous avons découvert que les sous unités chaperons du protéasome 19S, Rpt6 et Rpt4, augmentent l'agrégation de la protéine Huntingtine dans les cellules, alors que la réduction du niveau de Rpt6 par ARN interférence diminue la quantité de Huntingtine agrégée. Si la Huntingtine mutante est adressée au protéasome de manière ubiquitine indépendante, elle est très facilement dégradée. L'agrégation des protéines Huntingtine mutante n'est pas la conséquence d'une inhibition de l'activité protéolytique du protéasome mais fait suite à un découplage entre l'activité de dépliement médiée par le protéasome 19S et l'activité protéolytique du protéasome 20S. Ces travaux révèlent le rôle clef de l'environnement cellulaire et particulièrement du protéasome 19S dans le mécanisme d'agrégation des protéines à expansion de polyglutamine.</abstract></profileDesc></hal></record>Pour manipuler ce document sous Unix (Dilib)
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