Evaluating the gut-brain axis of Parkinson's disease pathogenesis and exploring potential therapies
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Parkinson’s Disease is a neurodegenerative illness of the central nervous system that impacts both cognitive and motor functioning. Current understanding dictates that these symptoms are caused by the death of dopaminergic neurons within the substantia nigra pars compacta of the basal ganglia. This neuronal death explains part of the symptoms, but large clumps of insoluble protein called Lewy Bodies are thought to also contribute. The α-synuclein (α-SN) protein is a major component of Lewy Bodies and has long been demonstrated to misfold and become aggregated. Classically, these Lewy Bodies first appear within the brainstem and spread upwards towards the cortex as the pathology progresses. While there have been some suggestions, the mechanism whereby α-SN misfolds in the brainstem is not currently understood. Additionally, the interplay between Lewy Bodies and dopaminergic neuronal death has not yet been discovered. One of the leading theories of α-SN misfolding is related to the gut-brain axis. Our gastrointestinal tract is innervated by the enteric nervous system, which sends signals to the brainstem via the vagus nerve. Curiously, α-SN is expressed within enteroendocrine cells of the intestine. These cells have connections to nerve fibers of the enteric nervous system at their basal lamina. The hypothesis reasons that some pathogenic agent can gain access to the cells of the intestine, cause α-SN to misfold, and cause this damaged protein to be transported within the vagus nerve. As the vagus nerve ultimately connects to the brainstem, this is where the Lewy Bodies are deposited to initiate Parkinson’s disease. Research has investigated this connection thoroughly but has yet to determine definitively if this gut-brain axis is truly causing pathology within the brainstem. This thesis attempts to provide an overview of the current literature relating to Parkinson’s disease as well as the current knowledge of the gut-brain axis. Then, this will evaluate the various entities proposed to be the unknown pathogen of the gut-brain axis and discuss some of the controversies in the literature. Finally, this thesis will discuss the therapies that have arisen from the concept of the gut-brain axis and the potential further directions that these therapies imply for research.
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