Publikationsserver der Universitätsbibliothek Marburg
Titel:Verhaltensauffälligkeiten transgener Mäuse mit defizienter kooperativer DNA-Bindung des Transkriptionsfaktors STAT1
Autor:Haussmann, Jan
Weitere Beteiligte: Meyer, Thomas (Prof. Dr. mult.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0323
URN: urn:nbn:de:hebis:04-z2013-03238
DOI: https://doi.org/10.17192/z2013.0323
DDC:610 Medizin
Titel (trans.):Behavioral changes in transgenic mice with deficient cooperative DNA-binding of the transcription factor STAT1
Publikationsdatum:2013-06-17
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Interferon-Gamma STAT1 behavior depression, Interferon-Gamma STAT1 Verhalten Depression

Zusammenfassung:
Zytokine spielen in der Pathogenese der humanen Depression eine zentrale Rolle; dafür sprechen die Beobachtung depressiver Reaktionen als klinische Nebenwirkung im Zu- sammenhang mit einer Interferon-α-Therapie und die erhöhten Serumspiegel einiger inflammatorischer Zytokine bei Depressionserkrankten. In der vorliegenden Arbeit wurde die Bedeutung der kooperativen DNA-Bindung des Transkriptionsfaktor STAT1 (Signaltransduktor und Aktivator der Transkription 1) für die Entstehung einer Depres- sion untersucht. Der Austausch eines kritischen Aminosäurerestes in der amino- terminalen Proteindomäne (F77A) bewirkt über eine Inhibition der Tetramerbildung und eine reduzierte Tyrosin-Dephosphorylierung von STAT1 eine Suppression der tran- skriptionellen Aktivierung von Interferon-γ-responsiven Zielgenen, wie dem mig1-Gen. In Verhaltensexperimenten unter Verwendung eines Knockin-Mausmodells zeigten homozygote transgene STAT1F77A/F77A-Mäuse einen depressionsassoziierten Phänotyp im Forced-Swim-Test ohne besondere Auffälligkeiten in lokomotions- und angstprü- fenden Testreihen. Der STAT1F77A/F77A-Genotyp besitzt einen protektiven Effekt auf das Überleben nach intraperitonealer Lipopolysaccharid-(LPS)-Injektion der transgenen Mäuse und bewirkte eine verstärkte Beeinträchtigung des Krankheitsverhaltens in einem frühen Stadium mit verkürzter Rekonvaleszenzsphase. Zusammenfassend bewirkt die fehlende kooperative DNA-Bindung von STAT1 einen depressionsassoziierten Phä- notyp mit gleichzeitigem Überlebensvorteil nach isolierter LPS-Gabe. Diese unerwarteten Resultate sprechen dafür, dass Interferon-γ, im strikten Gegensatz zu Typ-I-Interferonen, antidepressiogene Effekte ausübt und dass diese über STAT1 vermittelt werden.

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