Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by neuromuscular junction decay, motor neuron death, progressive paralysis, and eventually death of the individual, usually by respiratory failure. Oxidative stress is a prominent hallmark of the disease and is often accompanied and exacerbated by mitochondrial dysfunction and neuroinflammation. This dissertation examines the role of glial cell senescence, a potential mechanism underlying oxidative stress in ALS. Microglia play a prominent role in ALS pathology. The data presented here provide the first evidence that microglia of transgenic rats bearing an ALS phenotype undergo senescence, which becomes more pronounced as the disease progresses, and is also associated with aberrant glial cell phenotypes.
The dissertation also highlights the importance of glutathione in the disease process and how alterations in glutathione metabolism eventually fail to compensate for accumulating oxidative damage. This revelation informed development of a novel glutathione derivative as a potential therapeutic for ALS and other diseases, where oxidative stress and glutathione loss combine to impair proper cellular function. The new derivative was created by altering glutathione disulfide through esterification of the carboxylic acid groups, followed by conjugation of 4-(Carboxybutyl)triphenylphosphonium bromide (TPP), a mitochondrial targeting moiety, to the amino groups. A further modification exchanged the bromide counterion for a mesylate group to enhance the water solubility of the glutathione derivative.
Finally, as a first step in the characterization of this new therapeutic, nuclear magnetic resonance (NMR) was used to study the dynamics of the derivatives in solution. Glutathione is a relatively flexible molecule in solution. This study demonstrated that the esterification of glutathione carboxylic acids and amino group coupling with TPP significantly reduce the motion of mitochondrially- targeted glutathione.
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