Advisory Committee Chair
Gail V W Johnson
Advisory Committee Members
Michael Brenner
Richard S Jope
Mathieu J Lesort
Elizabeth S Sztul
Document Type
Dissertation
Date of Award
2008
Abstract
Alzheimer’s disease (AD), the most common neurodegenerative disease, is pathologically characterized by senile plaques composed of amyloid β peptide and neurofibrillary tangles composed of hyperphosphorylated and aberrantly cleaved microtubule-associated protein tau. Numerous studies have demonstrated the critical importance of tau in AD pathogenesis; however, the mechanisms involved in the regulation of tau functions by posttranslational modifications of tau and by other cellular factors need to be further elucidated. The first part of my study focused on how posttranslational modifications of tau, specifically, site-specific phosphorylation and C-terminal cleavage, regulate its physiological function in associating with cytoskeleton, binding to and stabilizing microtubules as well as its pathological function in aggregation. Using pseudophosphorylation and truncation to mimic tau phosphorylation and cleavage, respectively, my work elucidated the differential effects of individual tau modifications on tau functions. In light of the importance of intermediate tau forms preceding the tangle formation in mediating tau dysfunction, in the second part of my study, I established a β-galactosidase complementation assay as a novel tool to examine early stage tau self-association in situ. The relative strength of tau-tau interactions was reflected by the activity of complementing β-galactosidase, which was detected by histochemistry and quantified by chemiluminescent assays. Treatment with lithium attenuated tau-tau interactions shown by decreased β-galactosidase activity, suggesting that this assay can be applied to study the regulation of tau self-associations by various cellular factors. Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that likely plays a role in neurodegeneration. In the last part of my study, I defined tau as a novel interacting protein of HDAC6 and revealed dual roles of HDAC6 in regulating tau phosphorylation and possibly aggregation. I also observed the presence of HDAC6 in AD pathology and upregulation of HDAC6 protein levels in AD brains. This work provided the first evidence that HDAC6 is involved in the pathogenesis of AD. Although these studies expanded our knowledge of mechanisms in the regulation of tau functions, further investigations are needed to fully understand the relationship of tau phosphorylation, cleavage and aggregation and to provide deep mechanistic insight into the functional consequences of HDAC6-tau interaction.
Recommended Citation
Ding, Huiping, "Regulation of tau functions by posttranslational modifications of tau and histone deacetylase 6" (2008). All ETDs from UAB. 6809.
https://digitalcommons.library.uab.edu/etd-collection/6809