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You searched for subject:(Caspases metabolism 60). Showing records 1 – 3 of 3 total matches.

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1. Matthews, Tori A. Pathological modifications of tau induce toxicity and facilitate cell death.

Degree: PhD, 2009, University of Alabama – Birmingham

lzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by two major pathophysiological hallmarks, beta-amyloid (A[Beta]) plaques and tau tangles. In AD and other tau associated neurodegenerative disorders, termed tauopathies, a critical role in promoting neuronal degeneration has been demonstrated for hyperphosphorylated forms of tau. Recent findings suggest that cleavage of tau in the carboxyl-terminal region (Asp421) may also promote deleterious effects of tau on neuronal health. In the first half of my study, the relationship between Asp421 cleaved tau and a common AD associated stressor (endoplasmic reticulum [ER] stress) was investigated using an inducible cortical neuronal model. Cells expressing Asp421 tau presented with higher levels of toxicity as compared to cells expressing the full-length protein, even before induction of ER stress. Under ER stress conditions, toxicity was significantly enhanced in Asp421 tau expressing cells. The differences in toxicity were underscored by alterations in caspase activation and cytokine signaling. In the second study, the effect of Asp421 tau expression on mitochondrial function was examined. Mitochondria in cells expressing Asp421 tau showed a shortened and rounded morphology, suggesting fragmentation. Additionally, mitochondrial function was severely inhibited in these cells as demonstrated by mitochondrial membrane potential loss and decreased calcium buffering ability in response to elevated intracellular calcium levels. Further, mitochondria in Asp421 tau cells exhibited increased levels of reactive oxygen species (ROS). Taken together the results suggest that Asp421 tau may negatively impact mitochondrial functioning in affected neurons in AD and other tauopathies, and promote disease progression. Given the importance of proper mitochondrial functioning in maintaining neuronal health, further studies are warranted in order to fully elucidate the mechanisms underlying this toxicity.

1 online resource (x, 105 p. : ill., digital, PDF file)

Cell Biology;

Joint Health Sciences;

tau caspases Alzheimer's disease

UNRESTRICTED

Advisors/Committee Members: Johnson, Gail V. W., Jope, Richard S.<br>, Lesort, Mathieu J.<br>, Sztul, Elizabeth S.<br>, Yoder, Bradley K..

Subjects/Keywords: Caspases  – metabolism<; br>; Cell Death  – physiology<; br>; Microtubules  – metabolism<; br>; tau Proteins  – physiology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Matthews, T. A. (2009). Pathological modifications of tau induce toxicity and facilitate cell death. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,607

Chicago Manual of Style (16th Edition):

Matthews, Tori A. “Pathological modifications of tau induce toxicity and facilitate cell death.” 2009. Doctoral Dissertation, University of Alabama – Birmingham. Accessed December 11, 2019. http://contentdm.mhsl.uab.edu/u?/etd,607.

MLA Handbook (7th Edition):

Matthews, Tori A. “Pathological modifications of tau induce toxicity and facilitate cell death.” 2009. Web. 11 Dec 2019.

Vancouver:

Matthews TA. Pathological modifications of tau induce toxicity and facilitate cell death. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2009. [cited 2019 Dec 11]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,607.

Council of Science Editors:

Matthews TA. Pathological modifications of tau induce toxicity and facilitate cell death. [Doctoral Dissertation]. University of Alabama – Birmingham; 2009. Available from: http://contentdm.mhsl.uab.edu/u?/etd,607

2. Dolan, Philip J. The role of post-translational modifications and valosin-containing protein in the turnover and stability of the microtubule-associated protein tau.

Degree: PhD, 2010, University of Alabama – Birmingham

Alzheimer Disease (AD) is pathologically characterized by the appearance of senile plaques composed of β-amyloid (Aβ) 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 Cterminal 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 doxycyclineiv 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 posttranslationally modified forms of tau.

1 online resource (x, 138 p.) : ill., digital, PDF file.

Cell Biology;

Joint Health Sciences;

tau VCP proteasome caspase microtubule

UNRESTRICTED

Advisors/Committee Members: Johnson, Gail V. W., Jope, Richard S.<br>, Roth, Kevin A.<br>, Sztul, Elizabeth<br>, Wilson, Scott M..

Subjects/Keywords: Alzheimer Disease  – enzymology<; br>; Autophagy<; br>; Caspases  – metabolism<; br>; Protein Kinases  – metabolism<; br>; Signal Transduction<; br>; tau Proteins  – physiology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Dolan, P. J. (2010). The role of post-translational modifications and valosin-containing protein in the turnover and stability of the microtubule-associated protein tau. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,1090

Chicago Manual of Style (16th Edition):

Dolan, Philip J. “The role of post-translational modifications and valosin-containing protein in the turnover and stability of the microtubule-associated protein tau.” 2010. Doctoral Dissertation, University of Alabama – Birmingham. Accessed December 11, 2019. http://contentdm.mhsl.uab.edu/u?/etd,1090.

MLA Handbook (7th Edition):

Dolan, Philip J. “The role of post-translational modifications and valosin-containing protein in the turnover and stability of the microtubule-associated protein tau.” 2010. Web. 11 Dec 2019.

Vancouver:

Dolan PJ. The role of post-translational modifications and valosin-containing protein in the turnover and stability of the microtubule-associated protein tau. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2010. [cited 2019 Dec 11]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,1090.

Council of Science Editors:

Dolan PJ. The role of post-translational modifications and valosin-containing protein in the turnover and stability of the microtubule-associated protein tau. [Doctoral Dissertation]. University of Alabama – Birmingham; 2010. Available from: http://contentdm.mhsl.uab.edu/u?/etd,1090

3. Ding, Huiping. Regulation of tau functions by posttranslational modifications of tau and histone deacetylase 6.

Degree: PhD, 2008, University of Alabama – Birmingham

Alzheimer’s disease (AD), the most common neurodegenerative disease, is pathologically characterized by senile plaques composed of amyloid [beta] 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 [beta]-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 [beta]-galactosidase, which was detected by histochemistry and quantified by chemiluminescent assays. Treatment with lithium attenuated tau-tau interactions shown by decreased [beta]-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.

viii, 137 p. : ill., digital, PDF file

Cell Biology

Joint Health Sciences

Alzheimer's Disease tau HDAC6 Neurodegeneration

UNRESTRICTED

Advisors/Committee Members: Johnson, Gail V. W., Brenner, Michael<br>Jope, Richard S.<br>Lesort, Mathieu J.<br>Sztul, Elizabeth S..

Subjects/Keywords: Alzheimer Disease  – metabolism<; br>; Brain  – metabolism<; br>; Caspases  – metabolism<; br>; Histone Deacetylases  – metabolism<; br>; Microtubules  – metabolism<; br>; Neurons  – metabolism<; br>; tau Proteins  – metabolism

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Ding, H. (2008). Regulation of tau functions by posttranslational modifications of tau and histone deacetylase 6. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,439

Chicago Manual of Style (16th Edition):

Ding, Huiping. “Regulation of tau functions by posttranslational modifications of tau and histone deacetylase 6.” 2008. Doctoral Dissertation, University of Alabama – Birmingham. Accessed December 11, 2019. http://contentdm.mhsl.uab.edu/u?/etd,439.

MLA Handbook (7th Edition):

Ding, Huiping. “Regulation of tau functions by posttranslational modifications of tau and histone deacetylase 6.” 2008. Web. 11 Dec 2019.

Vancouver:

Ding H. Regulation of tau functions by posttranslational modifications of tau and histone deacetylase 6. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2008. [cited 2019 Dec 11]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,439.

Council of Science Editors:

Ding H. Regulation of tau functions by posttranslational modifications of tau and histone deacetylase 6. [Doctoral Dissertation]. University of Alabama – Birmingham; 2008. Available from: http://contentdm.mhsl.uab.edu/u?/etd,439

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