Molecular mechanisms of cellular dysfunction caused by a tauopathy-associated fragment

Abstract

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.

Date of Award	2019
Original language	English
Awarding Institution	King's College London
Supervisor	Diane Hanger (Supervisor) & Wendy Noble (Supervisor)