Annonacin, ein natürlicher Komplex-I Inhibitor, erhöht die Tau-Phosphorylierung im Gehirn von FTDP-17 transgenen Mäusen

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,...

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Bibliographic Details
Main Author: Respondek, Gesine
Contributors: Oertel, W. H. (Prof. Dr. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2014
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Table of Contents: Tauopathies are a pathologically defined group of neurodegenerative diseases whose hallmark is the aggregation of hyperphosphorylated tau, a microtubule-associated protein. Tauopathies represent a very heterogeneous entity with regard to their clinical picture and their etiology. The exact mechanisms that lead to the development of these diseases are unclear. An example of an environmentally caused tauopathy is the atypical Parkinson syndrome endemic in the Caribbean island of Guadeloupe, linked to high consumption of fruits or infusion of leaves of Annonaceae species (Caparros-Lefèbvre and Elbaz et al., 1999; Champy et al., 2005; Lannuzel et al., 2007). Annonacin is a natural mitochondrial toxin that inhibits complex I of the mitochondrial respiratory chain, that was shown to cause neuronal death and tau pathology in in vitro and in vivo experiments (Lannuzel et al., 2003; Champy et al., 2004; Escobar-Khondiker et al., 2007). On the other hand, many mutations in the tau gene have been associated with familial cases of tauopathies, such as the frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17). Although it is widely accepted that both genetic and environmental factors are likely to contribute to the observed neurodegenerative lesions, it remains unclear how specific genetic backgrounds affect the susceptibility towards the exposure to environmental toxins. We aimed to investigate gene-environment interactions using experimental models of tau-associated neurodegeneration. We proposed to determine whether there was a pathogenic synergy between annonacin intoxication and a mutation in the tau gene that leads to FTDP-17. We used transgenic mice bearing the R406W FTDP-17 mutation to study the effects of annonacinon the tau protein.