Document Type

Dissertation

Date of Award

5-2008

Keywords

neurosciences

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Steven P. Tammariello

Second Advisor

Susannah Gal

Third Advisor

Robert Van Buskirk; Karl Wilson

Subject Heading(s)

Nervous system -- Degeneration; NAD(P)H dehydrogenases; Oxidases; Cell differentiation; Apoptosis

Abstract

Neuronal differentiation is an important process during human development and regenerative medicine. One factor linked to differentiation of neurons in vivo as well as in vitro is the generation of reactive oxygen species (ROS). In addition, neurodegeneration is the disease of the old age that is currently affecting millions. Although the etiology of each neurodegenerative disease differs, oxidative stress has been the common factor leading to neuronal death. PC12 cells differentiate into sympathetic-like neurons in the presence of nerve growth factor (NGF). Once terminally differentiated, PC12 cells undergo apoptosis following NGF deprivation with similar characteristics of sympathetic neuronal death. These properties make them useful for studying in vitro neuronal differentiation and apoptosis. In addition, NADPH oxidase has been implicated in the differentiation and apoptosis of this cell line through production of reactive oxygen species (ROS). However, the subunits involved in both processes have not been identified. A series of studies were designed to examine the effect of physiological activator (angiotensin II) and pharmacological inhibitor (DPI) of NADPH oxidase on PC12 cell differentiation and apoptosis. The differentiation study has revealed that the putative subunits involved in the early phases may be Nox4 and p67-phox, with subsequent recruitment of Nox1 and p47-phox during the later stages of differentiation. NGF withdrawal led to an increase in Nox1, p47-phox and p67-phox suggesting a role for those subunits in PC12 cell apoptosis. Therefore, these data confirm and extend previous results that suggest that neuronal but not phagocytic NADPH oxidase is involved in neurogenesis and apoptosis.

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