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ROLE OF NEURONAL NITRIC OXIDE SYNTHASE IN AGING AND
NEURODEGENERATION
by
Yeung Lam
_____________________________________________________________________
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)
December 2007
Copyright 2007 Yeung Lam
Object Description
| Title | Role of neuronal nitric oxide synthase in aging and neurodegeneration |
| Author | Lam, Yeung |
| Author email | ylam@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology & Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2007-10-23 |
| Date submitted | 2007 |
| Restricted until | Restricted until 5 Nov. 2009. |
| Date published | 2009-11-05 |
| Advisor (committee chair) | Cadenas, Enrique |
| Advisor (committee member) |
Alkana, Ronald Hodis, Howard |
| Abstract | Nitric oxide synthase (NOS) is a flavin- and heme- containing enzyme that catalyzes the metabolism of L-arginine to L-citrulline and nitric oxide (.NO) in the presence of O2 and NADPH. Neuronal NOS (nNOS) is a Ca2+-calmodulin-dependent isoform of NOS that is constitutively expressed in neuronal cells. The cellular level of nNOS is regulatory by its turnover through degradation by the proteasome. Various studies have demonstrated that proteasome activity declines with age. Furthermore, dysfunction proteasome is implicated in Parkinson's disease (PD) in which the formation of Lewy bodies and a progressive degeneration of dopaminergic neurons are observed. However, to date, there has been no extensive study undertaken to investigate the role of proteasome function, aging, and nNOS level with respect to viability of dopaminergic neuron. Here, we propose that aging-induced dysfunction of proteasome leads to accumulation of nNOS protein, thereby increasing the production of reactive nitrogen species (RNS), such as .NO and peroxynitrite (ONOO-), and thus results in neuronal death due to increased nitrative / nitrosative stress. In this dissertation, by using brains from rats of different age and a PC12 dopaminergic cell model, it is demonstrated that nNOS protein levels increased with age and this correlated with an increase in both nitrosative and nitrative stress. Under conditions of elevated nNOS expression, two important mitochondrial enzymes involved in mitochondria bioenergetics, succinyl-CoA:3-oxoacid CoA-transferase (SCOT) and F1-ATPase, were found to be nitrated. Nitration of SCOT and F1-ATPase lead to a decrease in their activities, thus suggesting a compromised energy production at the level of reducing-equivalent generation and oxidative phosphorylation, respectively.; The consequences of declined energy production were linked to increased apoptosis as shown by enhanced cytochrome c release in aged brain. Data from the PC12 model suggests that aging-induced dysfunction or impairment of the proteasome system leads to enhanced expression of nNOS which concomitant .NO production and ONOOformation. The latter activated c-Jun N-terminal Kinase (JNK). JNK induces phosphorylation of BclXL (inhibition) eventually triggered the activation of downstream apoptosis cascade that included the commitment (caspase-9) and execution (capase-3) phase. The cytotoxic consequences of an enhanced nNOSactivity was further supported by an enhanced activation of paraquat (a potent herbicide) in rat brain homogenates and PC12 cell lysates, leading to decreased cell viability. Inhibition of nNOS activity abolished the formation of paraquat radical, thus suggesting the important role of nNOS in environmental toxin-induced sporadic Parkinsonism. Data presented herein this dissertation strongly supports the notion that the age-related elevation of nNOS may contribute to the increased nitric oxidemediated neuronal cell death, which is inherent in to progression of the pathophysiology of PD. |
| Keyword | neurodegeneration; nitric oxide synthase; nitric oxide; mitochondria |
| 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-m905 |
| Rights | Lam, Yeung |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Lam-20071105 |
| Archival file | uscthesesreloadpub_Volume48/etd-Lam-20071105.pdf |
Description
| Title | Page 1 |
| Full text | ROLE OF NEURONAL NITRIC OXIDE SYNTHASE IN AGING AND NEURODEGENERATION by Yeung Lam _____________________________________________________________________ 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) December 2007 Copyright 2007 Yeung Lam |
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