Date of Award

2017-01-01

Degree Name

Master of Science

Department

Biological Sciences

Advisor(s)

Sukla Roychowdhury

Abstract

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 a 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 Gβγ, an important component of the G protein-signaling pathway, induces neuronal outgrowth and differentiation by modulating microtubule (MT) assembly, and 4-NP interferes with this process. 4-NP has been shown to inhibit neurotrophin-dependent neurite formation and cellular aggregation in cultured PC12 cells. 4-NP also inhibited neurite outgrowth of Gβγ-overexpressed PC12 cells. Based on these results, I hypothesize that 4-NP inhibits neurite outgrowth and induces neurodegeneration by disrupting MTs and associated proteins through Gβγ mediated pathway. PC12 cells were used for this 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 inhibited tubulin expression, disrupted polymer-monomer equilibrium and MT organization, and inhibited MT-Gβγ interactions in NGF-differentiated PC12 cells. In Specific Aim 2, I have conducted the proteomic analysis of 4-NP treated cells and found that the compound affected the cytoskeletal profile in NGF-differentiated PC12 cells. Principle Component analysis (PCA) using Scaffold-Perspective software showed that 4-NP significantly affected the protein composition/pattern of CSK in NGF-differentiated PC12 cells. In summary, I concluded that one of the mechanisms by which 4-NP causes neuronal damage is by altering the Gβγ-cytoskeletal mediated pathway, which is critical for neuronal growth and development.

Language

en

Provenance

Received from ProQuest

File Size

63 pages

File Format

application/pdf

Rights Holder

Cynthia Carreon

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