Date of Award

2013-01-01

Degree Name

Master of Science

Department

Biological Sciences

Advisor(s)

Sukla Rochowdhury

Second Advisor

Siddhartha Das

Abstract

Neurodegeneration, a progressive loss of nerve cells (neurons), occurs in many neurological disorders including Alzheimer's disease, Parkinson's disease, Schizophrenia, and drug addiction. Cytoskeletal disruption in neurons and aggregation of proteins associated with these disorders is the hallmark of neurodegeneration. However, the cause of neurodegenerative disorders is unknown and currently there are no effective drug treatments. Aging is the most consistent risk factor for developing a neurodegenerative disorder, and recent evidence suggests that environmental factors, which act as endocrine disruptors, pose a risk in the disease process. 4- nonylphenol (4-NP), an endocrine-disrupting compound (EDC), has been shown to affect brain development and may cause neurodegeneration. In the environment, 4-NP arises as a degradation product of alkylphenol polyethoxylates, compounds widely used as nonionic surfactants in commercial production, as well as in herbicides, pesticides, polystyrene plastics, and paints and has been shown to undergo high level of accumulation in biological tissues. However, the mechanism by which 4-NP exerts its effect is not understood. Recent results from our laboratory indicate that Gbetagamma, an important component of the G protein-signaling pathway, induces neurite outgrowth and that the interactions of Gbetagamma with microtubules (MTs), an important component of the cytoskeleton, is important for this process. Furthermore, we found that blocking the Gbetagamma-MT interaction induces neurodegeneration. The goal of the present research is to determine whether 4-NP inhibits neurite outgrowth and induces neurodegeneration by altering the Gbetagamma-MT- mediated pathway, and if other cytoskeletal components are involved in this process. Pheochromocytoma (PC12) cells were used to conduct the study because they respond to nerve growth factor (NGF) and exhibit a typical phenotype of neurons. In Specific Aim 1, using biochemical, pharmacological, and immunoconfocal methodologies, I have demonstrated that 4- NP inhibits neurite outgrowth and induces neurodegeneration by altering MT-Gbetagamma interaction in PC12 cells. In Specific Aim 2, I have conducted the proteomic analysis of 4-NP treated cells and found that the compound affects the cytoskeletal profile in NGF-differentiated PC12 cells. In conclusion, I propose that one of the mechanisms by which 4-NP causes neuronal damage is by altering the Gbetagamma-cytoskeletal mediated pathway, which is critical for neuronal growth and development.

Language

en

Provenance

Received from ProQuest

File Size

64 pages

File Format

application/pdf

Rights Holder

Jessica Martinez Jurado

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