Role of Narp in L-DOPA-induced dyskinesia
Identifieur interne : 000971 ( Hal/Corpus ); précédent : 000970; suivant : 000972Role of Narp in L-DOPA-induced dyskinesia
Auteurs : Marion MalerbiSource :
Descripteurs français
- mix :
- 6-Ohda, Dyskinésies, L-Dopa, Narp, Striatum.
English descriptors
- mix :
Abstract
Dopaminergic replacement therapy in Parkinson’s disease is hampered by the occurrence of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID result from L-DOPA-induced aberrant plasticity in the striatum due to modifications of the transcriptional program. Using a microarray-based approach, we identified Narp as a putative candidate implicated in LID induction. Thus, we investigated Narp involvement in LID by examining abnormal involuntary movements (AIM) development in Narp genetically-ablated mice or upon intrastriatal injection of a dominant negative form of Narp. Interestingly, the total AIM score was greatly reduced in these two models of impaired Narp expression. Hence, my results highlight Narp as an important actor in LID development. Then, I further examined Narp regulatory mechanisms in the striatum and I demonstrated that dopamine stimulation leads to increased Narp expression both at the transcriptional level and at the protein level through its accumulation within the synaptic compartment. These findings advance knowledge about mechanisms underlying dyskinesia with the hope of delaying their appearance in patients.
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Hal:tel-01133511Le document en format XML
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One major hypothesis is that LID result from L-DOPA-induced aberrant plasticity in the striatum due to modifications of the transcriptional program. Using a microarray-based approach, we identified Narp as a putative candidate implicated in LID induction. Thus, we investigated Narp involvement in LID by examining abnormal involuntary movements (AIM) development in Narp genetically-ablated mice or upon intrastriatal injection of a dominant negative form of Narp. Interestingly, the total AIM score was greatly reduced in these two models of impaired Narp expression. Hence, my results highlight Narp as an important actor in LID development. Then, I further examined Narp regulatory mechanisms in the striatum and I demonstrated that dopamine stimulation leads to increased Narp expression both at the transcriptional level and at the protein level through its accumulation within the synaptic compartment. These findings advance knowledge about mechanisms underlying dyskinesia with the hope of delaying their appearance in patients.</div></front></TEI><hal api="V3"><titleStmt><title xml:lang="en">Role of Narp in L-DOPA-induced dyskinesia</title><title xml:lang="fr">Rôle de Narp dans le développement des dyskinésies induites par la L-DOPA</title><author role="aut"><persName><forename type="first">Marion</forename><surname>Malerbi</surname></persName><idno type="halauthorid">1146706</idno><idno type="IdRef">http://www.idref.fr/184398320</idno><affiliation ref="#struct-246044"></affiliation></author><editor role="depositor"><persName><forename>ABES</forename><surname>STAR</surname></persName><email type="md5">f5aa7f563b02bb6adbba7496989af39a</email><email type="domain">abes.fr</email></editor></titleStmt><editionStmt><edition n="v1" type="current"><date type="whenSubmitted">2015-03-19 15:07:05</date><date type="whenModified">2015-03-21 01:03:05</date><date type="whenReleased">2015-03-20 11:40:20</date><date type="whenProduced">2015-01-30</date><date type="whenEndEmbargoed">2015-03-19</date><ref type="file" target="https://tel.archives-ouvertes.fr/tel-01133511/document"><date notBefore="2015-03-19"></date></ref><ref type="file" subtype="author" n="1" target="https://tel.archives-ouvertes.fr/tel-01133511/file/2015PA066025.pdf"><date notBefore="2015-03-19"></date></ref></edition><respStmt><resp>contributor</resp><name key="131274"><persName><forename>ABES</forename><surname>STAR</surname></persName><email type="md5">f5aa7f563b02bb6adbba7496989af39a</email><email type="domain">abes.fr</email></name></respStmt></editionStmt><publicationStmt><distributor>CCSD</distributor><idno type="halId">tel-01133511</idno><idno type="halUri">https://tel.archives-ouvertes.fr/tel-01133511</idno><idno type="halBibtex">malerbi:tel-01133511</idno><idno type="halRefHtml">Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2015. Français. <NNT : 2015PA066025></idno><idno type="halRef">Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2015. Français. <NNT : 2015PA066025></idno></publicationStmt><seriesStmt><idno type="stamp" n="STAR">STAR - Dépôt national des thèses électroniques</idno><idno type="stamp" n="CNRS">CNRS - Centre national de la recherche scientifique</idno><idno type="stamp" n="UPMC">Université Pierre et Marie Curie</idno><idno type="stamp" n="ICM" p="UPMC">Institut du Cerveau et de la Moëlle Epinière</idno><idno type="stamp" n="THESES-UPMC">Thèses de l'Université Pierre et Marie Curie</idno><idno type="stamp" n="APHP" p="INSERM">AP-HP</idno></seriesStmt><notesStmt></notesStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Role of Narp in L-DOPA-induced dyskinesia</title><title xml:lang="fr">Rôle de Narp dans le développement des dyskinésies induites par la L-DOPA</title><author role="aut"><persName><forename type="first">Marion</forename><surname>Malerbi</surname></persName><idno type="halauthorid">1146706</idno><idno type="IdRef">http://www.idref.fr/184398320</idno><affiliation ref="#struct-246044"></affiliation></author></analytic><monogr><idno type="nnt">2015PA066025</idno><imprint><date type="dateDefended">2015-01-30</date></imprint><authority type="institution">Université Pierre et Marie Curie - Paris VI</authority><authority type="school">Cerveau, cognition et comportement (3C)</authority><authority type="supervisor">Jean-Christophe Corvol</authority><authority type="jury">Emmanuel Valjent</authority><authority type="jury">Pierre-Olivier Fernagut</authority><authority type="jury">Jocelyne Caboche</authority><authority type="jury">Lydia Kerkerian-Le-Goff</authority><authority type="jury">Denis Herve</authority></monogr></biblStruct></sourceDesc><profileDesc><langUsage><language ident="fr">French</language></langUsage><textClass><keywords scheme="author"><term xml:lang="en">Dyskinesia</term><term xml:lang="en">Parkinson</term><term xml:lang="fr">6-Ohda</term><term xml:lang="fr">Striatum</term><term xml:lang="fr">L-Dopa</term><term xml:lang="fr">Dyskinésies</term><term xml:lang="fr">Narp</term></keywords><classCode scheme="halDomain" n="sdv.neu">Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]</classCode><classCode scheme="halTypology" n="THESE">Theses</classCode></textClass><abstract xml:lang="en">Dopaminergic replacement therapy in Parkinson’s disease is hampered by the occurrence of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID result from L-DOPA-induced aberrant plasticity in the striatum due to modifications of the transcriptional program. Using a microarray-based approach, we identified Narp as a putative candidate implicated in LID induction. Thus, we investigated Narp involvement in LID by examining abnormal involuntary movements (AIM) development in Narp genetically-ablated mice or upon intrastriatal injection of a dominant negative form of Narp. Interestingly, the total AIM score was greatly reduced in these two models of impaired Narp expression. Hence, my results highlight Narp as an important actor in LID development. Then, I further examined Narp regulatory mechanisms in the striatum and I demonstrated that dopamine stimulation leads to increased Narp expression both at the transcriptional level and at the protein level through its accumulation within the synaptic compartment. These findings advance knowledge about mechanisms underlying dyskinesia with the hope of delaying their appearance in patients.</abstract><abstract xml:lang="fr">Le traitement substitutif par la L-DOPA, indiqué dans la maladie de Parkinson, induit à terme des complications motrices appelées les dyskinésies induites par la L-DOPA. L'apparition des dyskinésies est due, au moins en partie, à la mise en place d'une plasticité aberrante dans le striatum, qui fait suite à des modifications transcriptionnelles induites par la L-DOPA. Une analyse du transcriptome nous a permis d'identifier le gène Nptx2, codant pour la neuropentraxine Narp, comme étant un candidat potentiellement impliqué dans l'apparition des dyskinésies. L'objectif de ce travail était d'étudier la régulation et le rôle de Narp dans l'apparition des dyskinésies, dans un modèle de souris lésée à la 6-hydroxydopamine. Nous avons montré que les dyskinésies induites par la L-DOPA sont diminuées chez des souris invalidées pour Nptx2 (Narp-KO). Par ailleurs, l'injection dans le striatum dorsal d'un adénovirus exprimant une forme dominante négative de Narp, induit une réduction importante des scores de dyskinésies. Dans le striatum, Narp est exprimé par les neurones épineux de taille moyenne et par les interneurones à parvalbumine. Après une stimulation dopaminergique, l'augmentation de l'expression de Nptx2 s'accompagne d'un enrichissement de Narp au niveau synaptique. Nos travaux montrent donc que Narp joue un rôle important dans le développement des dyskinésies et suggèrent qu'il pourrait être impliqué dans la plasticité synaptique des neurones du striatum, comme cela a été montré dans l'hippocampe. Ces résultats permettent d'ouvrir de nouvelles perspectives thérapeutiques pour retarder l'apparition de ces complications motrices chez les patients parkinsoniens.</abstract></profileDesc></hal></record>Pour manipuler ce document sous Unix (Dilib)
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