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.NO MEDIATED NEUROTOXICITY: REDOX CHANGES AND ENERGY FAILURE
IN A NERUOINFLAMMATORY MODEL
by
Li-Peng Yap
_____________________________________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
May 2008
Copyright 2008 Li-Peng Yap
Object Description
| Title | NO mediated neurotoxicity: redox changes and energy failure in a neuroinflammatory model |
| Author | Yap, Li-Peng |
| Author email | lipengya@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology & Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2008-03-20 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-04-18 |
| Advisor (committee chair) | Cadenas, Enrique |
| Advisor (committee member) |
Brinton, Roberta Diaz Kaplowitz, Neil |
| Abstract | The nefarious role of NO in neurodegenerative diseases such as Alzheimer's disease stems from the excessive production and labile nature of NO. The mechanisms of NO redox signaling through protein post translational modification is ill-defined in the neurodegenerative model. S-nitrosylation, which can be an intermediary step leading S-glutathionylation of proteins has emerged as a well characterized mechanism through which NO reversibly regulates cell function. However, there is little evidence concerning the regulation of S-glutathionylation of proteins by NO, which proteins are glutathionylated in neurons during nitrosative stress, and the consequence of glutathionylation of proteins on overall cellular and mitochondrial function. Therefore, the hypothesis to be tested is that nitric oxide generated during neuroinflammation leads to changes in cellular redox status and protein post translational modification which play a role in energy impairment leading to neuronal injury.; Our results indicate that acute exposure of neurons to NO, mirroring neuroinflammation, led to increase formation of ONOO-, oxidation of the cellular redox environment and the formation of S-glutathionylated proteins. Exposure to exogenous NO also resulted in an alteration of cellular redox status through the formation of intracellular GSNO and GSSG. Autoxidation of mitochondrial electron chain components elicited by NO resulted in the formation of a substantial portion of ONOO- in the inter membrane space and outside of mitochondria due to the release of O2.- from mitochondria even in the presence of NO. Hence, this increase in ROS and RNS formation by mitochondrial could modulate mitochondrial redox status by oxidizing GSH. Increasing concentrations of GSNO and GSSG formation as a consequence of NO exposure correlated with S-glutathionylation of proteins. Glutathonylation of GAPDH, a key glycolytic enzyme, led to significant inhibition of its activity. Mitochondrial energy substrate appear important for maintaining mitochondrial GSH and cellular viability as .NO mediated neurotoxicity was attenuated by the addition of a variety of mitochondrial energy substrates such as pyruvate, malate and beta-hydroxybutyrate. These observations delineate a potential mechanism through which increase .NO production, a key event in neurodegeneration, could potentially lead to protein S-glutathionylation and neuronal dysfunction seen inneurodegenerative diseases such as Friedreich's ataxia and Alzheimer's disease. |
| Keyword | neuroinflammation; nitric oxide; redox; protein post translational modification |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m1154 |
| Contributing entity | University of Southern California |
| Rights | Yap, Li-Peng |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Yap-20080418 |
| Archival file | uscthesesreloadpub_Volume17/etd-Yap-20080418.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | .NO MEDIATED NEUROTOXICITY: REDOX CHANGES AND ENERGY FAILURE IN A NERUOINFLAMMATORY MODEL by Li-Peng Yap _____________________________________________________________________ A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR PHARMACOLOGY AND TOXICOLOGY) May 2008 Copyright 2008 Li-Peng Yap |
