Degree Type

Dissertation

Date of Award

2017

Degree Name

Doctor of Philosophy

Department

Biomedical Sciences

Major

Toxicology

First Advisor

Anumantha G. Kanthasamy

Abstract

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder affecting about one million people in the United States and an estimated 10 million people worldwide. Although the pathological features of the disease, including dopaminergic neuronal loss and protein aggregation in the nigrostriatal tract are well understood, no cure or therapy exists that can decelerate or halt the neurodegenerative process. The exact mechanisms leading to cell death are still unresolved and advances in drug discovery for PD have been hampered by the lack of animal models that faithfully recapitulate the chronic, progressive nature of the disease, the full range of symptomology, and the underlying pathophysiological pathways. A recent transgenic mouse model, referred to as “MitoPark”, was created by selective inactivation of mitochondrial transcription factor A (TFAM) in the nigrostriatal pathway through control of the dopamine transporter (DAT) promotor by utilizing Cre/LoxP recombination. MitoPark mice model human PD by exhibiting a progressive course of the phenotypic manifestations and neurodegeneration, protein inclusions in nigral tissues, L-DOPA responsiveness, and adult-onset of disease. Considering that nonmotor symptoms reduce the quality of life and increase the cost of healthcare for PD patients, we characterized the full range of symptomatology in the MitoPark model. Similar to human PD, our MitoPark data suggest that many nonmotor symptoms, including cognitive deficits in learning and memory, olfactory discrimination, and neuropsychiatric deficits, are present in the model prior to severe motor dysfunction. Moreover, we have identified changes in neurogenesis, oxidative stress markers, and neurochemistry in the brain that correlate with the nonmotor symptoms observed. Furthermore, we have established that neuroinflammation (as a result of reactive microgliosis) and altered neurogenesis (subsequent to dopamine depletion) are present in later stages of the disease in this mouse model, making it particularly valuable for translational neurotoxicity and drug discovery studies. We also demonstrate that manganese, an environmentally relevant toxin linked to increased PD risk, can exacerbate some of these effects and accelerate disease onset in MitoPark mice. Finally, we explore two promising therapeutic options for PD: a mitochondrially targeted antioxidant and a neuroprotective protein. Our data demonstrate that Mito-apocynin treatment effectively attenuates progressive motor deficits, neuroinflammation, oxidative stress, and neurodegeneration in a comprehensive PD model via NOX2 inhibition in microglia and antioxidant effects in neurons. By expanding on recent work in our laboratory showing that Prokineticin-2 (PK2) serves a compensatory neuroprotective role in PD models, we identified a new mechanism by which PK2 may exert its effect: promoting neural stem cell proliferation and differentiation. Taken together, we have identified salient features of PD disease progression in a mouse model and applied the model to elucidate gene-environment interactions and to evaluate novel therapeutic strategies.

Copyright Owner

Monica Langley

Language

en

File Format

application/pdf

File Size

346 pages

Included in

Toxicology Commons

Share

COinS