Thesis (P.hD)) - University of Queensland, 2004. / Includes bibliography.

Thesis (Ph. D.)--University of Wisconsin, 1964. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Bibliography: leaves 249-258.

Thesis (M.A.) University of Missouri-Columbia, 2004. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (June 30, 2006) Vita. Includes bibliographical references.

Thesis (B.Sc)--University of Hong Kong, 2001. / "A dissertation submitted in partial fulfilment of the requirements for the Bachelor of Science (Speech and Hearing Sciences), The University of Hong Kong, May 4, 2001." Also available in print.

Thesis (M.M.) Florida State University, 2007. / Advisor: Jayne Standley, Florida State University, College of Music. Title and description from dissertation home page (viewed 8-29-2007). Document formatted into pages; contains 65 pages. Includes biographical sketch. Includes bibliographical references.

Thesis (M.Sc.)--University of Melbourne, School of Physiotherapy, 2009. / Typescript. Includes bibliographical references (leaves 107-116)

No description available.

α-Synuclein (αSyn) is a small intrinsically disordered protein that drives the progression of a group of neurological disorders known of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Increased expression of αSyn due to gene duplication or triplication causes familial forms of these diseases, of which the severity is positively correlated with the gene copy number. Despite extensive efforts using various models, the precise mechanisms of αSyn toxicity in neurons have not been elucidated. This could be partly due to biological differences between the models and authentic human neurons. In an attempt to model synucleinopathies with human neurons, I have established a collection of transgenic human embryonic stem cell (hESC) lines over-expressing αSyn. I first showed that elevated αSyn expression does not affect hESC proliferation and their differentiation potential towards neurons. Then I identified transgenic hESC lines that maintained high αSyn expression in differentiated neurons and compared the rate of reactive oxygen species (ROS) production in high versus normal αSyn expressing cortical neuronal cultures. I observed a significantly elevated level of ROS production in αSyn over-expressing neurons in less mature neurons; however, there was no difference observed in more mature neurons. The possible reasons that lead to this difference are discussed. This is the first report of stable αSyn overexpressing hESC lines, which can provide an unlimited source of human neurons for studying the mechanism underlying neuronal cell death in synucleinopathies, which in turn could lead to the development of potential therapeutics.

Leucine rich repeat kinase 2 (LRRK2) is a 286 kDa protein expressed in a variety of tissues and cell types, including neuronal tissue and innate immune cells. Mutations in LRRK2 have been linked to inflammatory diseases, most notably Crohn’s disease and Parkinson’s disease. Further to this, LRRK2 expression is induced by innate immune stimuli, and can be phosphorylated by Myd88 directed TLR signalling. Functional experiments were performed using macrophages from WT and LRRK2 knockout mice. Many phenotypes and interactions have been described for LRRK2 in a neuronal or in vitro context; therefore experiments in macrophages were specifically designed to investigate these phenotypes and interactions in an innate immune context. LRRK2 interacts with a range of small GTPase proteins called Rabs, which coordinate and carry out vesicular trafficking, including that of innate immune receptors. Further interactions have been shown with clathrin-mediated endocytic machinery and phagocytic machinery; including cytoskeletal components actin and tubulin. Accordingly, the role of LRRK2 in the expression, membrane localisation, and ligand-induced endocytosis of the innate immune receptors such as TLR4 were assayed. TLR4 plays an important role in immune responses to alpha-synuclein, an immunogenic protein aggregate that accumulates as part of Parkinson’s disease pathology, making it a particularly interesting target for this assay. No effect was shown for LRRK2 on TLR4 expression or receptor mediated endocytosis, so attention was focused upon LRRK2 cytoskeletal interactions. An unclear role of LRRK2 has been described in phagocytosis. Application of LRRK2 KO macrophages in a series of systematic phagocytosis assays was used to demonstrate and clarify that there is no role of LRRK2 in the phagocytosis of simple beads, opsonised material, or complex bacterial targets expressing a range of immunogenic molecules such as LPS. A genome wide approach was applied to further investigate the role of LRRK2 in TLR4 mediated signalling, as well as NOD2 mediated signalling. Comparison of LPS responses between WT and LRRK2 KO genotype macrophages identified a role of LRRK2 in modulating transcription of a range of chemokines and chemokine receptors. This indicates a specific role of LRRK2 in regulating chemotaxis in LPS stimulated cells. Knockout of LRRK2 resulted in a complete reversal of the regulation of the expression of EPAC1, a cAMP inducible protein working in parallel with a previously described LRRK2 interacting protein PKA. EPAC1 acts, at least in part, via Ca2+ signalling. Modulation of signalling through pathways such as Ca2+, Wnt and cAMP appear as a theme in results described in this transcriptomic experiment. A parallel metabolomic approach allowed analysis of ceramide levels in resting and innate immune stimulated macrophages. Ceramides are lipid molecules able to activate the NLRP3 inflammasome, as well as modulate alpha-synuclein pathology via ceramide metabolomic products. In contrast to results described in neuronal tissue, LRRK2 has no effect on ceramide levels in resting macrophages, however stimulation of NOD2 via MDP resulted in a dramatic LRRK2 specific increase in ceramide levels. Together, these results indicate a role of LRRK2 in activated innate immune cells.

This study was designed to inform theoretical and clinical understanding of the relation between executive function and metacognition in late adulthood, and to examine the effects of Parkinson's Disease (PD) on these aspects of the executive control system. The sample included two groups of neurologically intact (NI) participants and one group of participants with PD. All participants were over the age of 55 years and screened for dementia and depression. The NI young-old group included 22 participants between the ages of 56 and 74 years of age. A second group of 20 participants, between the ages of 75 and 90 years formed the NI old-old sample. The third group included 20 nondemented participants between the ages of 55 and 84 years with a diagnosis of PD. First on measures of executive function, memory, and motor performance significant age-related differences were limited. Tasks measuring the ability to generate novel concepts and to execute target motor movements revealed a significantly lower level of performance for the NI old-old participants, relative to their younger counterparts. While age-related differences in performance did not reach significance on the remaining tasks, the mean scores for the NI young-old group were slightly higher. The participants with PD had a lower level of performance than the NI groups in all three measured areas of functioning. Second, the three measures of metacognition, performance predictions, postdictions, and data each yielded distinctive results. The accuracy of predictions was largely resilient to the effects of aging. However, the prediction accuracy of the PD participants was lower on measures of memory and gross motor performance. Groups were equivalent on measures of postdiction accuracy across measures, with the exception of the handwriting task where the NI groups showed a higher level of accuracy than the PD group. Perceptions of daily memory functioning were similar for the three groups. However, the participants with PD reported more motor problems than those reported by the NI groups. Third, the results confirmed the theoretical relation between executive functioning and metacognition in the areas of memory and fine motor control, but executive function was found to have little impact on a more routine gross motor task. The relation between executive function and metacognition appears to be domain-specific, with a stronger association on cognitively-laden tasks relative to tasks of a more routine nature. / Graduate