Mechanisms of action of the homeoprotein Engrailed in midbrain dopaminergic neurons
Identifieur interne : 000642 ( Hal/Curation ); précédent : 000641; suivant : 000643Mechanisms of action of the homeoprotein Engrailed in midbrain dopaminergic neurons
Auteurs : Hocine Rekaik [France]Source :
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Abstract
Homeoproteins are a major class of transcription factors that exert some of their functions through non-cell autonomous activity, due to their ability to transfer between cells. Two of these homeoproteins, En1 and En2 (collectively Engrailed) are responsible for midbrain dopaminergic (mDA) neuron development, and maintenance during adulthood. En1+/- mice display a selective and progressive degeneration of the mDA neurons, reminiscent of Parkinson disease (PD). Engrailed infusion confers neurotection against cell death in several mouse models of PD, leading to the hypothesis that Engrailed could be implicated in the physiopathology of the disease. To dissect the mechanisms underlying Engrailed-mediated protection, the transcriptome of mDA neurons in En1+/- was analyzed. It was found that the loss of one En1 allele leads to severe alterations in the expression of DNA damage response and chromatin remodeling genes. The same alterations were detected and amplified in an acute mouse model of oxidative stress, suggesting that mDA neurons from En1+/- mice are less resistant to oxidative stress and, conversely, that Engrailed may protect them against oxidative stress. Indeed, Engrailed transduction into mDA neurons saves them from cell death and restores all DNA damage and epigenetic marks. A second mechanism neuroprotection by Engrailed concerns LINE-1 elements. These retrotransposons have the ability to create genomic instability through their endonuclease activity. Their direct repression by Engrailed could be part of a general protective activity against genomic instability.
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mésencéphale</title><author><name sortKey="Rekaik, Hocine" sort="Rekaik, Hocine" uniqKey="Rekaik H" first="Hocine" last="Rekaik">Hocine Rekaik</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-139750" status="VALID"> <orgName>Centre interdisciplinaire de recherche en biologie</orgName> <orgName type="acronym">CIRB</orgName> <desc> <address> <addrLine>11 place Marcellin Berthelot 75005 Paris</addrLine> <country key="FR"></country> </address> </desc> <listRelation> <relation active="#struct-300026" type="direct"></relation> <relation name="U1050" active="#struct-303623" type="direct"></relation> <relation name="UMR7241" active="#struct-441569" type="direct"></relation> </listRelation><tutelles><tutelle active="#struct-300026" type="direct"><org type="institution" xml:id="struct-300026" status="VALID"> <orgName>Collège de France</orgName> <desc> <address> <country key="FR"></country> </address> </desc></org></tutelle><tutelle name="U1050" 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</desc></org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author></analytic></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="mix" xml:lang="en"><term>Dopaminergic neuron</term><term>Oxidative stress</term><term>Parkinson</term></keywords><keywords scheme="mix" xml:lang="fr"><term>Engrailed</term><term>Instabilité génomique</term><term>Neurone dopaminergique</term><term>Rétrotransposon</term><term>Stress oxydatif</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Homeoproteins are a major class of transcription factors that exert some of their functions through non-cell autonomous activity, due to their ability to transfer between cells. Two of these homeoproteins, En1 and En2 (collectively Engrailed) are responsible for midbrain dopaminergic (mDA) neuron development, and maintenance during adulthood. En1+/- mice display a selective and progressive degeneration of the mDA neurons, reminiscent of Parkinson disease (PD). Engrailed infusion confers neurotection against cell death in several mouse models of PD, leading to the hypothesis that Engrailed could be implicated in the physiopathology of the disease. To dissect the mechanisms underlying Engrailed-mediated protection, the transcriptome of mDA neurons in En1+/- was analyzed. It was found that the loss of one En1 allele leads to severe alterations in the expression of DNA damage response and chromatin remodeling genes. The same alterations were detected and amplified in an acute mouse model of oxidative stress, suggesting that mDA neurons from En1+/- mice are less resistant to oxidative stress and, conversely, that Engrailed may protect them against oxidative stress. Indeed, Engrailed transduction into mDA neurons saves them from cell death and restores all DNA damage and epigenetic marks. A second mechanism neuroprotection by Engrailed concerns LINE-1 elements. These retrotransposons have the ability to create genomic instability through their endonuclease activity. Their direct repression by Engrailed could be part of a general protective activity against genomic instability.</div></front></TEI><hal api="V3"> <titleStmt> <title xml:lang="en">Mechanisms of action of the homeoprotein Engrailed in midbrain dopaminergic neurons</title> <title xml:lang="fr">Mécanismes d'action de l'homéoprotéine Engrailed dans les neurones dopaminergiques adultes du mésencéphale</title> <author role="aut"> <persName> <forename type="first">Hocine</forename> <surname>Rekaik</surname> </persName> <idno type="halauthorid">1466024</idno> <idno type="IdRef">http://www.idref.fr/197532950</idno> <affiliation ref="#struct-139750"></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">2017-01-23 11:47:07</date> <date type="whenModified">2017-01-30 09:49:38</date> <date type="whenReleased">2017-01-27 10:12:01</date> <date type="whenProduced">2016-09-27</date> <date type="whenEndEmbargoed">2017-01-23</date> <ref type="file" target="https://tel.archives-ouvertes.fr/tel-01443622/document"> <date notBefore="2017-01-23"></date> </ref> <ref type="file" subtype="author" n="1" target="https://tel.archives-ouvertes.fr/tel-01443622/file/these_archivage_3369294.pdf"> <date notBefore="2017-01-23"></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-01443622</idno> <idno type="halUri">https://tel.archives-ouvertes.fr/tel-01443622</idno> <idno type="halBibtex">rekaik:tel-01443622</idno> <idno type="halRefHtml">Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2016. Français. <NNT : 2016PA066257></idno> <idno type="halRef">Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2016. Français. <NNT : 2016PA066257></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="CDF">Collège de France</idno> <idno type="stamp" n="THESES-UPMC">Thèses de l'Université Pierre et Marie Curie</idno> <idno type="stamp" n="PSL">Paris Sciences et Lettres (PSL) Research University</idno> <idno type="stamp" n="INSERM">INSERM - Institut national de la santé et de la recherche médicale</idno> </seriesStmt> <notesStmt></notesStmt> <sourceDesc> <biblStruct> <analytic> <title xml:lang="en">Mechanisms of action of the homeoprotein Engrailed in midbrain dopaminergic neurons</title> <title xml:lang="fr">Mécanismes d'action de l'homéoprotéine Engrailed dans les neurones dopaminergiques adultes du mésencéphale</title> <author role="aut"> <persName> <forename type="first">Hocine</forename> <surname>Rekaik</surname> </persName> <idno type="halauthorid">1466024</idno> <idno type="IdRef">http://www.idref.fr/197532950</idno> <affiliation ref="#struct-139750"></affiliation> </author> </analytic> <monogr> <idno type="nnt">2016PA066257</idno> <imprint> <date type="dateDefended">2016-09-27</date> </imprint> <authority type="institution">Université Pierre et Marie Curie - Paris VI</authority> <authority type="school">École doctorale Cerveau, cognition, comportement (Paris)</authority> <authority type="supervisor">Rajiv Joshi</authority> <authority type="jury">Laure Bally-Cuif</authority> <authority type="jury">François Karch</authority> <authority type="jury">Patricia Gaspar</authority> <authority type="jury">Frédéric Saudou</authority> <authority type="jury">Alessandra Pierani</authority> <authority type="jury">Alain Prochiantz</authority> </monogr> </biblStruct> </sourceDesc> <profileDesc> <langUsage> <language ident="fr">French</language> </langUsage> <textClass> <keywords scheme="author"> <term xml:lang="en">Parkinson</term> <term xml:lang="en">Oxidative stress</term> <term xml:lang="en">Dopaminergic neuron</term> <term xml:lang="fr">Stress oxydatif</term> <term xml:lang="fr">Neurone dopaminergique</term> <term xml:lang="fr">Rétrotransposon</term> <term xml:lang="fr">Instabilité génomique</term> <term xml:lang="fr">Engrailed</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">Homeoproteins are a major class of transcription factors that exert some of their functions through non-cell autonomous activity, due to their ability to transfer between cells. Two of these homeoproteins, En1 and En2 (collectively Engrailed) are responsible for midbrain dopaminergic (mDA) neuron development, and maintenance during adulthood. En1+/- mice display a selective and progressive degeneration of the mDA neurons, reminiscent of Parkinson disease (PD). Engrailed infusion confers neurotection against cell death in several mouse models of PD, leading to the hypothesis that Engrailed could be implicated in the physiopathology of the disease. To dissect the mechanisms underlying Engrailed-mediated protection, the transcriptome of mDA neurons in En1+/- was analyzed. It was found that the loss of one En1 allele leads to severe alterations in the expression of DNA damage response and chromatin remodeling genes. The same alterations were detected and amplified in an acute mouse model of oxidative stress, suggesting that mDA neurons from En1+/- mice are less resistant to oxidative stress and, conversely, that Engrailed may protect them against oxidative stress. Indeed, Engrailed transduction into mDA neurons saves them from cell death and restores all DNA damage and epigenetic marks. A second mechanism neuroprotection by Engrailed concerns LINE-1 elements. These retrotransposons have the ability to create genomic instability through their endonuclease activity. Their direct repression by Engrailed could be part of a general protective activity against genomic instability.</abstract> <abstract xml:lang="fr">Les homéoprotéines sont des facteurs de transcription qui en plus de leur rôle important durant le développement des métazoaires, bénéficient de fonctions autonome et non autonome-cellulaire dans le cerveau adulte. Parmi ces homéoprotéines, Engrailed1/2 (collectivement Engrailed) est exprimée dans les neurones dopaminergiques mésencéphaliques adulte, ceux-là même qui dégénèrent dans la maladie de Parkinson. Chez les souris délétées d’une copie du gène (En1+/-), une dégénérescence progressive des neurones dopaminergiques s’accompagne de symptômes moteurs et non moteurs rappelant la maladie de Parkinson, ce qui pourrait faire de ces souris un modèle nouveau et intéressant de cette maladie neurodégénérative. Des expériences de transduction de la protéine En1 dans les cellules du mésencéphale de souris démontrent son effet neuroprotecteur dans des modèles toxicologiques de la maladie de Parkinson et chez les souris En1+/-, menant à l’hypothèse qu’Engrailed est important dans la physiopathologie de cette maladie. L’essentiel de ce travail de thèse s’inscrit dans la compréhension des mécanismes d’action de l’homéoprotéine Engrailed dans les neurones dopaminergiques mésencéphaliques. L’activité physiologique importante de ces neurones et le stress métabolique oxydant qui est généré touche plusieurs compartiments cellulaires, dont le noyau. La stabilité du génome semble être un aspect majeur de l’action d’Engrailed dans ces neurones. D’abord contre les effets délétères du stress oxydatif sur l’intégrité de l’ADN et la structure de la chromatine, ensuite, contre l’activité génotoxique des éléments transposables LINE-1.</abstract> </profileDesc> </hal></record>Pour manipuler ce document sous Unix (Dilib)
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