Date of Award

Fall 12-18-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Dr. R. Lee Mosley

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and second most common neurodegenerative disorder. PD is characterized by the selective loss of dopaminergic neurons and dopamine neurotransmitter within the substantia nigra and termini in the striatum. Progressive loss of dopaminergic neurons occurs over many years in PD, and by the time movement disorder symptoms manifest, up to 50-70% of dopaminergic neurons have been lost. Several aspects of PD pathology have been described in detail, but a better understanding of PD progression is needed to develop more efficient treatments.

Motor symptoms associated with PD do not manifest until significant numbers of dopaminergic neurons are lost, suggesting compensatory mechanisms play a role in maintaining normal motor function. However, little is known about these mechanisms and the role they play in delaying PD symptom onset.

Only palliative treatment is now available for PD. This consists of principally of dopamine replacement therapy and L-DOPA considered the gold treatment standard. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, chronic administration of dopamine replacement drugs, L-DOPA or BL-1023 in the absence of further degeneration, resulted in improved motor function and consistent increases in the number of TH+ neurons in the substantia nigra. The increase in TH+ neurons was not associated with dopaminergic neurogenic activity, but rather a phenotypic shift of GAD67+ GABAergic neurons to express TH. These data represent a novel effect of dopamine replacement therapy as triggering putative compensatory mechanisms, presumably to restore dopamine levels in a dopamine depleted environment.

An interleukin-23 (IL-23) knock-out mouse strain proven to have significantly reduced dopaminergic neuron population was used to test motor control and behavior. No significant differences were observed between knock-out and wild-type in any of the forced or unforced motor tests. These data suggest either insufficient dopaminergic loss to afford functional alterations or that compensation to the dopaminergic signaling pathway allowed for normal functioning.

Taken together, compensatory mechanisms represent a novel pathway for PD treatment that include symptomatic benefits as well as potential regenerative strategies. Targeting such pathways may provide more effective therapeutics by avoiding the secondary toxicities of current pharmaceuticals.