Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Harry Ischiropoulos

Second Advisor

Robert Kalb

Abstract

Neurodegenerative disorders are characterized by the death of specific neuronal populations and the aggregation of particular proteins into pathological inclusions. The role of protein aggregation and the factors that govern neuronal susceptibility to disease have remained unclear. In Parkinson’s disease (PD), the loss of dopamine producing neurons in the substantia nigra (SN) leads to severe motor impairments, and the protein α-synuclein is found aggregated in several brain regions including the SN. The goal of this thesis was to investigate a possible mechanism for the vulnerability of dopaminergic neurons: the interaction of α-synuclein with dopamine itself. While dopamine has been suspected to contribute to cell death in PD by causing oxidative stress, I found using a lentiviral approach that a long-term increase of dopamine levels in non-transgenic mice was insufficient to produce dopamine neuron loss. In contrast, elevating dopamine in mice expressing human α-synuclein resulted in progressive nigrostriatal degeneration and an associated locomotor deficit. These findings demonstrate that dopamine toxicity is dependent on α-synuclein. To explore a possible point of convergence of these two factors, I examined the effects of dopamine on α-synuclein aggregation in the mouse brain. This led to the novel observation that dopamine increases total steady-state levels of α-synuclein oligomers and promotes modified oligomeric conformations. α-Synuclein oligomers generated in the presence of dopamine in vitro were biochemically similar to mouse-derived species and were found to be toxic to primary neurons. Taken together, these data provide evidence that dopamine-induced α-synuclein oligomers may underlie the susceptibility of dopaminergic neurons in disease.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS