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Parkinson's Disease: Insights into Novel Astrocyte-Mediated Mechanisms of Dopaminergic Neurodegeneration
Parkinson's Disease (PD) is the second most common neurodegenerative disorder worldwide, with no known cure. The main pathological hallmark of PD is the loss of DA neurons within the substantia nigra pars compacta (SNc). The neurocentric approach to PD research has given us insight into intrinsic mechanisms by which DA neurons degenerate, however, considering the lack of therapeutic breakthroughs, it is imperative to consider the role that glia, particularly astrocytes, play in PD pathogenesis. Astrocytes are the most prominent cell type within the central nervous system (CNS) and were originally thought to only provide passive support for neurons. Emerging evidence has implicated astrocytes as an active contributor to CNS physiology via numerous mechanisms. One method by which astrocytes regulate brain activity is via the secretion of a plethora of molecules. While many of these molecules such as glutamate and ATP have known targets and cellular effects, it is important to consider the entirety of the astrocyte secretome and novel targets by which these molecules may modulate DA neuron physiology in the context of PD. Additionally, developing specific, targeted therapies for PD has been challenging because of the difficulty of drug delivery. Effective drug-delivery to the brain has been challenging due to the high selectivity of the blood-brain barrier (BBB), therefore it is also essential to develop novel methods, such as nanoparticles, to deliver therapeutic molecules across the BBB. In this dissertation, I focus on these barriers for developing novel PD treatments by understanding how pathological astrocyte-neuron interactions affect neurodegeneration and developing optimized drug delivery systems for targeted brain-region specific drug delivery. I specifically address these issues by: (i) Developing a primary midbrain astrocyte-neuron co-culture system to investigate astrocyte-neuron communication, (ii) Determine the effects of gold-coated superparamagnetic iron-oxide nanoparticles on DA neuron activity, (iii) Discover a novel mechanism by which extracellular astrocytic S100B modulates DA neuron physiology via voltage-gated ion channel activity, (iv) review evidence suggesting that calcium signals in astrocytes are an upstream regulator of their function, and (v) Show that MIF treatment following TBI contributes to increased CA1 hippocampal neuron activity and the sensitivity to glutamatergic astrocytes. The electronic version of this dissertation is accessible from https://hdl.handle.net/1969.1/198619
Doctor of Philosophy Texas A&M University 2022 https://hdl.handle.net/1969.1/198619