Advisory Committee Chair
Gail V Johnson
Advisory Committee Members
Richard S Jope
Kevin A Roth
Elizabeth Sztul
Scott Wilson
Document Type
Dissertation
Date of Award
2010
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Alzheimer Disease (AD) is pathologically characterized by the appearance of senile plaques composed of ß-amyloid and neurofibrillary tangles composed of the microtubule-associated protein tau. During the development of AD pathology, tau is hyperphosphorylated and aberrantly cleaved, both of which potentially contribute to its pathogenic and fibrillogenic nature. The accumulative nature of these post-translational products, and their contribution to tau pathology, has led to a great deal of study regarding mechanisms for both the maintenance of tau stability and degradation. The first part of this study reviews the developments regarding the contribution of phosphorylated tau to different physiological and pathological processes. Potential mechanisms of both kinase activation and phosphatases inhibition that might lead to increased tau phosphorylation are considered. The contribution of phosphorylated tau to microtubule stability, axonal transport, and aggregate formation are also described. Another pathogenic post-translational modification present in AD brain is the C-terminal truncation of tau at Asp421. In the second part of this study, the degradative pathway that engages this cleaved form of tau is studied. By using a doxycycline-inducible turnover assay, a prominent role for macroautophagy is described for the cleaved form of tau; this is in contrast to full-length tau, which undergoes proteasomal degradation. Because of the documented defects to the autophagy system in AD, it is plausible that this leads to accumulation of the pathogenic cleaved form of tau. Because of this dual degradative fate of tau dependent on post-translational processing, the third part of this study examines the potential role of the AAA+ protein VCP (known to be involved in both proteasomal and autophagic degradation) in the maintenance of tau stability. It was found that VCP levels are lowered in AD brain, and that lowered VCP levels leads to a loss of overall tau stability. However, the level of tau phosphorylated at Ser262 is increased. Ser262-phosphorylated tau has been shown to be a substrate of the macroautophagy system, indicating specific inhibition of macroautophagy as a result of lowered VCP levels. These studies expand our knowledge of the degradative fate of tau, but further studies are needed to more robustly examine the differential fate of other post-translationally modified forms of tau.
Recommended Citation
Dolan, Philip James, "The role of post-translational modifications and valosin-containing protein in the turnover and stability of the microtubule-associated protein tau" (2010). All ETDs from UAB. 1539.
https://digitalcommons.library.uab.edu/etd-collection/1539