Paget's disease of the bone is characterized by a focal increase in the rate of bone turnover, which goes through phases of activity and quiescence. Most patients are asymptomatic. The two cardinal features are pain and deformities, and many complications may arise. Diphosphonates and calcitonin are the main therapeutic modalities.

The mitochondrion is the powerhouse of the cell. Therefore, it is critical to the homeostasis of the cell that populations of mitochondria that are damaged or in excess are degraded. The process of targeted elimination of damaged or excess mitochondria by autophagy is called mitophagy. In this report, analysis of the mitophagy regulators PINK1/PARKIN and BNIP3L and their roles are assessed in the lens. PARKIN, an E3 ubiquitin ligase, has been shown to play a role in directing damaged mitochondria for degradation. While BNIP3L, an outer mitochondrial membrane protein, increases in expression in response to excess mitochondria and organelle degradation during cellular differentiation. We have shown that PARKIN is both induced and translocates from the cytoplasm to the mitochondria in human epithelial lens cells upon oxidative stress exposure. In addition, our findings also show that overexpression of BNIP3L causes premature clearance of mitochondria and other organelles, while loss of BNIP3L results in lack of clearance. Prior to this work, PARKIN mediated mitophagy had not been shown to act as a protective cellular response to oxidative stress in the lens. This project also resulted in the novel finding that BNIP3L-mediated mitophagy mechanisms are required for targeted organelle degradation in the lens. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2015 / FAU Electronic Theses and Dissertations Collection

by Rebecca McGreal. / Vita. / Thesis (Ph.D.)--Florida Atlantic University, 2012. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2012. Mode of access: World Wide Web. / The central premise of this dissertation is that the small heat shock protein (sHSP), (Sa(BB-crystallin is essential for lens and retinal pigmented epithelial (RPE) cell function and oxidative stress defense. To date, the mechanism by which it confers protection is not known. We hypothesize that these functions could occur through its ability to protect mitochondrial function in lens and RPE cells. To test this hypothesis, we examined the expression of (Sa(BB-crystallin/sHSP in lens and RPE cells, we observed its localization in the cells, we examined translocation to the mitochondria in these cells upon oxidative stress treatment, we determined its ability to form complexes with and protect cytochrome c (cyt c) against damage, and we observed its ability to preserve mitochondrial function under oxidative stress conditions in lens and RPE cells. In addition to these studies, we examined the effect of mutations of (Sa(BB-crystallin/sHSP on its cellular localization and translocation patterns under oxidative stress, its in vivo and in vitro chaperone activity, and its ability to protect cyt c against oxidation. Our data demonstrated that (Sa(BB-crystallin/sHSP is expressed at high levels in the mitochondria of lens and RPE cells and specifically translocates to the mitochondria under oxidative stress conditions. We demonstrate that (Sa(BB-crystallin/sHSP complexes with cyt c and protects it against oxidative inactivation. Finally, we demonstrate that (Sa(BB-crystallin/sHSP directly protects mitochondria against oxidative inactivation in lens and RPE cells. Since oxidative stress is a key component of lens cataract formation and age-related macular degeneration (AMD), these data provide a new paradigm for understanding the etiology of these diseases.

Fan Boli. / "January 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 219-248). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Polyglutamine disease is a class of neurodegenerative diseases, which is manifested by the atrophy of nervous system that results in dementia and/or motor dysfunction. The major pathological characteristics include progressive loss of neuronal cells as well as the appearance of insoluble nuclear inclusions in degenerating neuronal cells. Polyglutamine disease is caused by CAG triplet expansion in the genome. When translated, such expansion leads to the formation of expanded polyglutamine domain within the respective disease proteins and promotes abnormal protein conformational changes. Owing to their misfolded nature, the expanded polyglutamine proteins form insoluble nuclear inclusions. These insoluble nuclear inclusions are heterogeneous in nature, in which polyglutamine protein and molecular chaperones are the recruited components. All eukaryotic cells express molecular chaperones which function to mediate the proper folding of proteins. The recruitment of molecular chaperones into nuclear inclusions that contain misfolded triplet-expanded proteins strongly suggests the involvement of molecular chaperones in polyglutamine disease progression. It has been shown that over-expression of molecular chaperones in polyglutamine disease models can lead to a suppression of polyglutamine toxicity and a concomitant increase in the solubility of disease proteins, i.e. the solubility of polyglutamine disease protein is related to its toxicity. Intrigued by these observations, I aimed at elucidating the mechanism of polyglutamine disease pathogenesis by first studying the cellular regulation of endogenous chaperone expression in neurodegeneration in a transgenic Drosophila model of polyglutamine disease. A biphasic regulation of Hsp70 expression was observed, which the regulation was at the transcription level. Moreover, over-expression of Hsp70 could alter the endogenous Hsp70 protein and mRNA level of polyglutamine disease fly model. The study may help the understanding of how the chaperone expression is regulated under the effects of polyglutamine expression and thus to find out the mechanism of pathogenesis. In addition, cellular proteins that change in solubility other than disease protein will also be identified. Small heat shock proteins, glutathione S transferase and alpha 4 proteasome subunit, etc., showed change in solubility or expression by 2D gel electrophoresis analysis. Identifying the proteins that change in solubility or expression may help the finding of the interplay of proteins and thus the pathways involve in the mechanism of polyglutamine disease pathogenesis. Understanding pathogenic pathways can give ideas on how polyglutamine lead to the disease, up- or down-regulation of those protein interplays may provide direction and therapeutic candidates to suppress polyglutamine disease. / Huen Ngar Yee. / "September 2006." / Advisers: Ho Yin Chan; Siu Kai Kong. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1465. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 134-146). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

This project consists of three distinct, but sequential studies that explore the psychological factors and neuropathological substrates of metacognition or self-awareness among older adults. Study 1 examines the premorbid, psychological characteristics associated with metamemory—the mainstay of metacognitive research—in a healthy, community-dwelling cohort of older adults. Study 2 builds on these analyses, and examines the psychological characteristics associated with metacognition, more broadly, in a neurologic cohort of older adults with Essential Tremor (ET). Study 3, which utilizes post-mortem evaluations of participants from Study 2, goes beyond premorbid characteristics and examines whether distortions in metacognition are in part attributable to an underlying disease process. Findings demonstrated that psychological characteristics were associated with metacognitive accuracy in a healthy, community-dwelling cohort of older adults, but not among individuals with ET; further, distortions in metacognition among individuals with ET were better attributable to non-ET specific pathologies, such as amyloid β, neurofibrillary tangles, and regional-specific atrophy. This project underscores the importance of employing a biopsychosocial approach to understanding the factors that influence metacognition. Ultimately, by understanding and working effectively with awareness phenomena, there is a strong potential to reduce disability and enhance well-being.

No description available.

Bibliography: leaves [280]-301

Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. Nutritional and/or genetic disruptions in homocysteine metabolism can cause hyperhomocysteinemia. Mild methylenetetrahydrofolate reductase (MTHFR) deficiency due to the 677C → T mutation in the MTHFR gene is the most common genetic cause of hyperhomocysteinemia. The 677C → T variant is associated with an increased risk for neural tube defects, pregnancy complications, schizophrenia and Down syndrome, and with a decreased risk for colon cancer and leukemia. This variant is also a potential risk factor for vascular disease. Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications. We have generated mice with a knockout of the Mthfr gene. The Mthfr-deficient mice exhibit hyperhomocysteinemia and decreased methylation capacity. The Mthfr+/- mice appear normal, whereas the Mthfr-/- mice are smaller and have reduced survival. Abnormal external granule neuron development associated with increased cell death in the cerebellum was observed in the Mthfr-/- mice. / Evidence for cardiovascular pathology was obtained in several ways. Impaired aortic relaxation response to acetylcholine was seen in the Mthfr +/- mice fed a high methionine diet. Both Mthfr+/- and Mthfr-/- mice fed a low folate high methionine diet developed myocardial fibrosis in the left ventricle. Abnormal lipid deposition in the proximal portion of the aorta was observed in older Mthfr+/- and Mthfr-/- mice. After crossing Mthfr -deficient mice with apoE-null mice, we demonstrated that MTHFR deficiency promoted atherogenesis and its progression in the apoE-null mice. / Gene expression in brain of Mthfr-deficient mice was investigated via microarray analysis. Five genes with altered expression in the brain of Mthfr-/- mouse were validated by RT-PCR. In biochemical studies of human MTHFR, both FAD and folate were shown to stabilize the purified recombinant wild type and mutant MTHFRs from the baculovirus expression system against heat inactivation. The effect of folate appeared to be secondary to that of FAD, and S-adenosylmethionine (SAM) inhibited purified wild type and mutant MTHFRs with similar efficiency. / This dissertation will significantly contribute to our understanding of the role of MTHFR in human disease.

Bibliography: leaves [280]-301 / xiv, 317 leaves : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Pathology, 1984