Defense Date

7-31-2018

Graduation Date

Fall 12-21-2018

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Pharmacology

School

School of Pharmacy

Committee Chair

Dr. Rehana Leak

Committee Member

Dr. David Johnson

Committee Member

Dr. Jane Cavanaugh

Committee Member

Dr. Paula Witt-Enderby

Committee Member

Dr. John Stolz

Keywords

Parkinson's, Lewy, synuclein, olfactory, fibril, dementia

Abstract

Lewy body disorders are a family of neurological brain disorders associated with olfactory, motor, and cognitive deficits and are collectively defined as α-synucleinopathies, as they are characterized by hallmark “Lewy bodies” composed of aggregated, fibrillar α-synuclein. It is not certain but often posited that fibrillar α-synuclein seeds the progressive, self-propagating spread of Lewy pathology through neuroanatomical circuitry. Furthermore, the site of disease induction is still debated. In Aim I, we developed a novel protocol for generating reproducible and robust α-synucleinopathy in the limbic temporal lobe following infusions of preformed α-synuclein iv fibrils into the mouse olfactory bulb, which is frequently the first brain region to display Lewy pathology in humans. Our tract-tracer studies revealed that all areas displaying dense Lewy-like pathology were indeed connected to the induction site. The pattern of α-synucleinopathy resembled that of Stage IIb of Beach’s unified staging theory rather than Parkinson’s disease. In Aim 2, we observed that α-synucleinopathy also remained confined to the limbic connectome regardless of gender, age, or incubation period. Lewy pathology that developed in the ventral mesencephalon was confined to the ventral tegmental area, which is also associated with limbic functions. Furthermore, our studies are the first to show that females are more resistant to the development of α-synucleinopathy and neurodegeneration than males, and that fibril infusions hastened mortality in aged mice. In Aim 3, N-acetyl cysteine protected primary neuron cultures against proteotoxicity, including that of α-synuclein fibrils, and the mechanism appeared to be partly dependent on the chaperone activity of heat shock protein 70. These findings were expanded to an in vivo study, in which mice were fed N-acetyl cysteine for 90 days after induction of olfactory α-synucleinopathy. Oral N-acetyl cysteine reduced Lewy-like pathology, but only in the anterior olfactory nucleus, the area of densest α-synucleinopathy in this model. In conclusion, we have developed a robust model of early-stage Lewy body disorders that appears to mimic the higher risk of Lewy body disorders in men and the acceleration of mortality with aging in these conditions.

Language

English

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