Dokument

Zusammenfassung:
Tauopathien sind eine Gruppe von neurodegenerativen Erkrankungen, die durch die Akkumulation von hyperphosphoryliertem Tau, einem Mikrotubuli-assoziierten Protein, gekennzeichnet sind. Sie stellen in Hinblick auf ihre Klinik und Ätiologie ein heterogenes Krankheitsbild dar. Die genauen Mechanismen, die zu der Entstehung der Erkrankungen führen, sind noch ungeklärt. Eine Tauopathie, die als vorwiegend umweltbedingt gilt, kommt auf der karibischen Inselgruppe Guadeloupe vor und konnte Einblicke in die Entstehung von Tau-Pathologie zugrunde liegenden Pathomechanismen liefern. Es gibt Hinweise, dass die Entstehung dieser Tauopathie mit dem Konsum der Früchte und Blätter des dort beheimateten Baumes Annona muricata und dem enthaltenen Toxin Annonacin in Zusammenhang steht (Caparros-Lefebvre und Elbaz et al., 1999; Champy et al., 2005; Lannuzel et al., 2007). Annonacin ist ein Inhibitor von Komplex-I der mitochondrialen Atmungskette, der experimentell in vitro und in vivo zu neuronalem Untergang und Tau-Pathologie führt (Lannuzel et al., 2003; Champy et al., 2004; Escobar-Khondiker et al., 2007). Auf der anderen Seite gibt es hereditäre Tauopathien, wie die Frontotemporalen Demenzen mit Parkinsonismus und Kopplung an das Chromosom 17 (FTDP-17). Verschiedene Mutationen im MAPT Gen, die meist durch ein autosomal-dominantes Muster vererbt werden, führen bei dieser Gruppe zur Entstehung der typischen Tau-Pathologie. Die bislang durchgeführten Untersuchungen konnten nicht klären, ob Annonacin die Hyperphosphorylierung des Tau-Proteins, wie sie in Tauopathien anzutreffen ist, reproduziert und inwieweit eine genetische Veränderung des Tau-Proteins diesen Effekt begünstigt. In der vorliegenden Studie bedienten wir uns zur Lösung dieser Fragestellung des Komplex-1-Inhibitors Annonacin und eines transgenen Mausmodelles, das humanes Tau mit der R406W-Mutation überexprimiert.

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