Defense Date

9-20-2016

Graduation Date

Fall 1-1-2016

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Pharmacology

School

McAnulty College and Graduate School of Liberal Arts

Committee Chair

Rehana Leak, David Johnson

Committee Member

Paula Witt-Enderby

Committee Member

Jane Cavanaugh

Committee Member

Robert Gibbs

Committee Member

James Drennen

Abstract

Parkinson’s disease is a progressive neurodegenerative disorder associated with disruptions in motor as well as non-motor functions, such as cognitive and olfactory impairments. Postmortem tissue from Parkinson’s patients shows evidence of oxidative stress in dopaminergic neurons and hallmark proteinaceous inclusions known as Lewy bodies in multiple brain regions spanning the medulla oblongata to the telencephalon. There are no therapies that decelerate the progression of this disease. Thus, the major goal of the present study was to test the therapeutic potential of two neuroprotective molecules, the antioxidant thiol N-acetyl-L-cysteine (NAC) and the steroid neuromodulator dehyroepiandrosterone sulfate (DHEAS), in experimental models of Parkinson’s disease in vivo. To accomplish this goal, we first established multiple animal models of Parkinson’s disease that mimicked oxidative and/or proteotoxic stress: the 6-hydroxydopamine (6-OHDA) model of dopaminergic neurodegeneration and the alpha-synuclein model of Lewy-like pathology. NAC offered only transient protection in the 6-OHDA model, as demonstrated by multiple histological techniques that were validated in the present study. Indeed, NAC was mildly toxic at doses previously employed in the clinic, with implications for the long-term use of NAC in patients with chronic neurodegenerative conditions. We also developed a model of Lewy-like pathology in the hippocampus in which to examine the effects of DHEAS upon memory function. Although DHEAS failed to affect memory, we subsequently discovered that infusions of waterbath-sonicated alpha-synuclein fibrils into hippocampal CA2/CA3 led to robust Lewy-like pathology in some (but not all) of the brain regions that send first-order efferent projections to the hippocampus—the amygdala, entorhinal cortex, and contralateral CA3. Similar to the human condition, we collected evidence of selective vulnerability to alpha-synucleinopathy, as the septohippocampal projections were spared in our model. Notably, Lewy-like pathology in the hippocampus was statistically correlated with memory and olfactory deficits. Taken together, these studies reveal a novel model of proteinopathy in the hippocampus, which is known to develop Lewy pathology at mid-to-end stages of Parkinson’s disease and may be partly responsible for cognitive deficits in this condition. This model can now be used to test neuroprotective drug candidates that have the potential to ameliorate proteinopathic stress and improve neurological outcomes.

Format

PDF

Language

English

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