Date of Award

12-31-2015

Document Type

Campus Access Thesis

Degree Name

Master of Science (MS)

Department

Biotechnology and Biomedical Science

First Advisor

Alexia Pollack

Second Advisor

Kenneth L. Campbell

Third Advisor

Gregory Beck

Abstract

Parkinson’s disease (PD) is a progressive, degenerative, neurological disease, which is classified primarily as movement disorder, although cognitive functioning is also often involved. PD is the second most common neurodegenerative disorder of aging – after Alzheimer’s disease (AD). The progressive disability associated with PD results in substantial burdens for those with the condition, their families, and society. Currently, there is no cure for PD and available pharmacological treatment often decline in effectiveness as the disease progresses. While the cause(s) of PD have not been well established, it has been hypothesized that genetic–, and especially environmental factors, such as pesticides, play significant roles. Therefore, understanding how environmental factors contribute to PD may help provide information about the disease mechanisms that could be used to prevent and or treat PD.

The task of identifying causative environmental agents responsible for idiopathic PD has proven difficult. Most studies have focused on events or treatments occurring during adulthood. The possibility that early exposure to pesticides leads to adult onset PD suggests that it is important to examine environmental exposure in early stages of development. The main aim of the proposed study is to examine whether developmental (juvenile) exposure of mice to the toxin benomyl – could result in neurotoxicity to the midbrain dopamine (DA) system, and could also increase vulnerability of DA neurons to subsequent neurotoxic challenges later in life (adult). Benomyl’s proposed mechanism of action is inhibition of aldehyde dehydrogenase (ALDH) enzymatic activity, which is a pathogenic mechanism implicated as a contributing factor to PD. This thesis describes and proposes a study that will measure striatal DA levels and ALDH activities between benomyl treatment groups – mice exposed as juveniles or adults, as well as examine brain sections at the level of the substantia nigra (SN) for α-synuclein aggregation – as a marker of Lewy bodies (LB) in the PD process. It is expected that there will be differences between benomyl-treated and untreated (controls) animals in these measures, and possibly differences between benomyl-treated juvenile and adult mice – suggesting that developmental exposure to benomyl may be important in the etiology of PD . Possible confounding problems to drawing definitive conclusions from the proposed study are also discussed, such as issues of silent toxicity, the duration and timing of benomyl treatments, and the compensatory capacity of the nervous system following benomyl treatment.

The results of the proposed study may provide a potential link between benomyl exposure or ALDH inhibition during development and increased risk of DA neurodegeneration. This link may be indicative of the fact that greater attention should be focused on the role of early life exposure to toxins in the development of PD.

Comments

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