Stone, Aelfwin
(2025)
Investigation of Triose Phosphate Isomerase dysfunction and Redox Stress in a Drosophila Melanogaster model of Neurodegenerative Disease.
PhD thesis, University of Nottingham.
Abstract
Neurodegenerative diseases have been extensively associated with increased redox stress, often this is linked to aberrant production of reactive species such as advanced glycation end products (AGEs). AGEs, and smaller reactive species like nitric oxide (NO), have been shown to increase redox stress, promoting protein and DNA modification, often via post translational modifications such as 3-Nitrotyrosination. Triose phosphate isomerase (TPI) is one protein that has been shown to undergo such modifications. TPI is an important, but non-essential, glycolytic enzyme whose main role is in the conversion of dihydroxyacetone phosphate (DHAP) to glyceraldyhyde-3-phosphate (G3P). This is an important conversion as it controls levels of methylglyoxal (MGO) which when increased significantly has also been directly linked to increased redox stress, protein modification, and DNA modification via AGE production. Thus, TPI dysfunction has been reported to lead to increased redox stress, enhancing glycation signalling, neuroinflammation, and neurodegeneration, and to be sensitive to redox stress itself, containing multiple sites for 3-nitrotyrosination. The resulting physiological mechanisms of TPI dysfunction are not yet well understood. TPI dysfunction has in turn been linked to various neurodegenerative disorders, including Alzheimer’s disease. Glyoxalase (Glo) is another key enzyme which provides an innate protective mechanism against MGO build up. This work aims to use Drosophila melanogaster to identify impacts of altered TPI on neuronal physiology linking aberrant TPI function and redox stress to synaptic deficits at the glutamatergic Drosophila neuromuscular junction (NMJ). A Drosophila mutant expressing reduced Glo activity is also reported to further investigate this metabolic pathway, and subsequent connection to neurodegeneration. Electrophysiology and immunohistochemistry, among other techniques, are utilised to investigate this pathology.
This work suggests that the phenotype arising from dysfunctional TPI is in part due to altered vesicle dynamics, possibly in vesicle pool organisation of the presynaptic neuron or endo/exocytosis, thus expanding our knowledge of the resultant mechanisms of TPI dysfunction. The data presented here implies that there are various mechanisms of dysfunction, likely to be via exacerbated redox stress, and compensatory mechanisms, suggested to be primarily via altered vesicle dynamics, leading to distinct pathologies with different mutations of the TPI protein. Impaired TPI and Glo activity are suggested to enhance protein glycation, redox stress, and post translational modifications, implying a possible route of pathology and presenting a potential target for therapies.
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