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Title: Molecular mechanisms underlying the development of tau pathology caused by tau fragmentation
Author: Guo, Tong
ISNI:       0000 0004 7963 905X
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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The tauopathies are a group of neurodegenerative diseases characterised by pathological changes in tau protein along with synaptic dysfunction, breakdown in neuronal connectivity and neuronal cell death. Evidence has shown a link between tau fragmentation and the tauopathies. However, the role of this post translational modification in the development of disease is still unclear. This thesis describes the pathological consequences of N-terminal cleavage of tau in a cell model stably expressing a human brain-derived, 35 kDa tau fragment (Tau35). Compared to full length human tau protein, Tau35 displayed several loss-of-function defects such as reduced microtubule binding affinity, failure to regulate microtubule organisation, and reduced acetylation of tubulin. Inhibiting the phosphorylation of Tau35 does not enhance the microtubule binding affinity of Tau35, suggesting the role of the N-terminal half of tau in mediating the tau-microtubule interaction. Moreover, missing of the N-terminus of tau reduced but did not abolish the association between tau and cytoplasmic membrane. On the other hand, this tau fragment also gained a series of pathological features, including aberrant phosphorylation, but insoluble tau aggregates are absent. Meanwhile, expression of Tau35 triggered activation of the unfolded protein response in cells, and disrupted the regulation of the Akt-GSK3β pathway. My results therefore revealed that apart from the long-proven importance of microtubule binding repeats in the C-terminal half of tau in mediating tau-microtubule interactions, the N-terminus of tau is also involved in these processes. Moreover, after deletion of the N-terminus, the resultant tau fragment, Tau35 not only loses the ability to execute the physiological function of tau as a microtubule stabiliser, but also interrupts the unfolded protein response and GSK3β pathways which in turn drive further pathological changes of Tau35. In summary, my findings provide a greater understanding of the role of tau fragmentation in the progression of tau pathology, and the novel Tau35 cell model will aid the understanding of disease-associated mechanisms and the development of novel treatments for human tauopathies.
Supervisor: Hanger, Diane Pamela ; Noble, Wendy Jane Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available