Interaction of Tau protein with Microtubules in neural cells

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Titel: Interaction of Tau protein with Microtubules in neural cells
Autor(en): Brühmann, Jörg
Erstgutachter: Prof. Dr. Roland Brandt
Zweitgutachter: Prof. Dr. Christian Ungermann
Zusammenfassung: The molecular dynamic of tau protein, its interaction with microtubules and the changes in both that appear in pathological conditions are a focus of research to get an insight in neurodegeneration. It is known that tau binds to microtubules by four homologous repeats in its carboxyterminal half. We want to examine tau and especially its repeat regions and their role for microtubule-interaction in living neurons using live cell imaging. We created multiple tau fragments with different numbers of repeats and expressed them in neuronal differentiated PC12 cells as a model for neurons. We performed fluorescence decay after photoactivation experiments by measuring the change of fluorescence intensity over time in the activated region in the middle of cell processes. From this experiments we were able to determine association and dissociation rates of the respective constructs by fitting and modeling approaches. Fluorescence decay increased with decreasing number of repeats. We found that a minimum number of three repeats required for microtubule interaction. This could also be observed in the tip of the processes. Destabilization of microtubules by colchicine increases the mobility of full length tau and microtubule-interacting fragments, while stabilization with epothilone D has no effect. Pseudophosphorylation of tau does not significantly affect the fluorescence decay, but leads to an increase of the dissociation and association rate. Truncation of the carboyxterminus after amino acid 421 - which simulates caspase 3 cleavage of tau - or amino acid 401 leads to a decrease of fluorescence decay indicating increased binding of these fragments to microtubules and a higher dissociation rate of these fragments. Furthermore we could show that overexpression of full length tau in PC12 cells increases the fraction of polymerized tubulin. The stronger binding caspase cleavage fragment shows a similar microtubule stabilization.
Schlagworte: Tau; Microtubules
Erscheinungsdatum: 22-Mai-2014
Enthalten in den Sammlungen:FB05 - E-Dissertationen

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