Dokument

Zusammenfassung:
Die Parkinson-Erkrankung ist die zweithäufigste neurodegenerative Erkrankung nach der Alzheimer-Demenz. In industrialisierten Ländern liegt die Prävalenz der Erkrankung bei knapp zwei Prozent für alle Personen über 65 Jahren. Klinisch ist die Erkrankung charakterisiert durch Bradykinese, Rigor, Ruhetremor und posturale Instabilität. Diese motorischen Symptome sind hauptsächlich durch einen Verlust dopaminerger Neurone in der Substantia nigra pars compacta verursacht. Das histopathologische Kennzeichen der Parkinson-Krankheit ist die Präsenz von intraneuronalen Einschlüssen, sogenannten Lewy-Körperchen, in überlebenden Neuronen der Substantia nigra pars compacta. Die Hauptkomponente der Lewy-Körperchen ist Alpha-Synuklein, ein Protein bestehend aus 140 Aminosäuren. Sinnverändernde Mutationen, Duplikationen und Triplikationen des Alpha-Synuklein-Gens führen zu seltenen genetischen Parkinson-Syndromen. Zudem haben genomweite Assoziationsstudien eine Vielzahl an Risikogenvarianten des Alpha-Synuklein-Gens als Risikofaktor für die Parkinson-Krankheit identifiziert. Aus diesen Gründen ist es heutzutage unbestritten, dass Alpha-Synuklein eine zentrale Rolle in der Entstehung der Parkinson-Krankheit spielt; allerdings ist weiterhin unklar, welche Alpha-Synuklein-Form die Neurodegeneration vermittelt. Bislang lindert die pharmakologische Therapie lediglich die Symptome der Parkinson-Krankheit und es existiert keine Therapie, die die Progression der Erkrankung nachweisbar verzögert oder gar aufhält. In unserer Forschungsgruppe wurde ein neues Zellkulturmodell der Parkinson-Krankheit entwickelt, in welchem die Überexpression des Alpha-Synuklein-Wildtyps durch adenovirale Transduktion zum Zelltod von humanen, postmitotischen, dopaminergen Neuronen (LUHMES-Zellen) führt. Ein Prozess der zellulären Homöostase um pathologische intrazelluläre Einschlüsse abzubauen, ist die Makroautophagie. Ziel dieser Dissertation war es deswegen zu untersuchen, ob Trifluoperazin, ein bekannter Aktivator der Makroautophagie in Neuronen, dopaminerge Zellen vor Wildtyp-Alpha-Synuklein-induzierter Toxizität schützen kann. Zunächst wurde durch Western-Blot-Analysen gezeigt, dass Trifluoperazin Makroautophagie auch in den hier verwendeten LUHMES-Neuronen aktiviert. Anschließend konnte nachgewiesen werden, dass diese Substanz tatsächlich die Zellen dosisabhängig vor Alpha-Synuklein-vermitteltem Zelltod schützt. Die dazu verwendeten Auswertungsmethoden umfassten die Messung der LDH-Konzentration im Zellkulturmedium sowie das Auszählen vitaler Zellen und apoptotischer Zellen nach der Zellfixierung und Färbung mittels DAPI. Die Überexpression von Wildtyp-Alpha-Synuklein führte zusätzlich zur Toxizität auch zum Erscheinen einer 37-kDa-Alpha-Synuklein-Western-Blot-Bande, welche in nicht-transduzierten Zellen nicht nachweisbar war. Interessanterweise konnte die Intensität dieser 37-kDa-Alpha-Synuklein-Bande durch Behandlung mit Trifluoperazin spezifisch und dosisabhängig reduziert werden, ohne die restlichen Alpha-Synuklein-Banden signifikant zu verändern. Chloroquin, ein Inhibitor der Autophagie, verstärkte passend dazu sowohl die Alpha-Synuklein-induzierte Toxizität als auch die 37-kDa-Alpha-Synuklein-Bande. Es ergab sich eine signifikante positive Korrelation zwischen der Toxizität und der Stärke dieser Western-Blot-Bande. Diese Daten legen den Schluss nahe, dass diese oligomerische Alpha-Synuklein-Bande eine Schlüsselrolle in der Alpha-Synuklein-vermittelten Toxizität zumindest innerhalb dieses Zellkulturmodells der Parkinson-Krankheit einnimmt. Der eigene Einfluss von Alpha-Synuklein auf die Makroautophagie (aktivierend oder hemmend) ist nach wie vor nicht vollständig geklärt. Die Ergebnisse der in dieser Dissertation durchgeführten Experimente lassen die Interpretation zu, dass eine Überexpression des Alpha-Synuklein-Wildtyps die Makroautophagie hemmt. Die Kernaussage dieser Doktorarbeit ist, dass die Aktivierung der Autophagie humane, postmitotische, dopaminerge Zellen vor Wildtyp-Alpha-Synuklein-induzierter Toxizität durch Abbau einer spezifischen Alpha-Synuklein-Form schützt. Diese Ergebnisse unterstützen die These, dass Autophagie-Aktivierung einen möglichen Ansatz in der Therapie der Parkinson-Krankheit darstellt. Zudem wurde eine 37-kDa-Alpha-Synuklein-Bande mittels Western Blot identifiziert, welche womöglich auch in der Pathogenese der Parkinson-Krankheit eine Rolle spielt.

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