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Title: Molecular mechanisms of cellular dysfunction caused by a tauopathy-associated fragment
Author: Dakkak, Dina
ISNI:       0000 0004 7963 9439
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Tauopathies are a group of neurodegenerative diseases characterised by cognitive and motor dysfunction, and pathological aggregates of abnormally phosphorylated and cleaved tau, a microtubule associated protein. Whilst the cause of these pathological changes is unknown, it is likely to be a combination of toxic gain-of-function acquired by aggregated tau, along with a loss of normal function of tau. This laboratory previously identified a form of cleaved tau (Tau35) in post-mortem human tauopathy brain and has developed animal and cell models expressing Tau35 to investigate molecular mechanism underlying tauopathy. These models include a transgenic mouse expressing Tau35 in low amounts, and Chinese hamster ovary (CHO) cells stably expressing Tau35 (CHO-Tau35) or full-length human tau (CHO-FL). This thesis aims to determine how Tau35 affects molecular mechanisms involved in tau metabolism, including the unfolded protein response (UPR) and autophagic/lysosomal degradation. In aged Tau35 mice, there was evidence of a toxic gain of function, including increased tau phosphorylation at disease-relevant epitopes in multiple brain regions. In addition, Tau35 mice exhibit activation of the UPR in specific brain regions. In CHO-Tau35 cells, a significant reduction in basal autophagy was identified, which was not apparent in either untransfected CHO cells or in CHO-FL cells expressing full-length tau, suggesting that Tau35 expression results in defective autophagy. Under conditions that stimulate autophagy, CHO-Tau35 cells exhibited a reduced capacity to activate mTOR-mediated autophagy and reduced autophagic flux. Conversely, expression of Tau35 promoted activation of autophagy through an mTOR-independent mechanism. Furthermore, inhibition of glycogen synthase kinase-3 rescued the defective autophagy in CHO-Tau35 cells. Notably, CHO-Tau35 cells exhibited a reduction in the number of lysosomes, as well as defective lysosomal functionality and a deficit in lysosome biogenesis compared to CHO-FL and untransfected CHO cells. Taken together, these findings suggest novel mechanisms through which the presence of Tau35, a tau fragment associated with the development of human tauopathy, exerts a detrimental effect on cells and provides insights into the significance of protein degradation systems in the development of tauopathy.
Supervisor: Hanger, Diane Pamela ; Noble, Wendy Jane Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available