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FUNCTIONAL PROTEOMIC ANALYSIS OF ALTERED PROTEIN SIGNALING MODULES IN ALZHEIMER’S DISEASE
by
Stefani Nicole Cottrell Thomas
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
(PHARMACEUTICAL SCIENCES)
May 2007
Copyright 2007 Stefani Nicole Cottrell Thomas
Object Description
| Title | Functional proteomic analysis of altered protein signaling modules in Alzheimer's disease |
| Author | Thomas, Stefani Nicole Cottrell |
| Author email | stefanit@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2007-03-07 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-03-28 |
| Advisor (committee chair) | Shen, Wei-Chiang |
| Advisor (committee member) |
Yang, Austin Ann, David K. Schauwecker, P. Elyse Okamoto, Curtis Toshio |
| Abstract | Neuritic plaques comprised of amyloid ß (Aß) are one of the primary neuropathological hallmarks of Alzheimer's disease (AD). However, Aß plaque deposition is preceded by aberrations of the endosomal/lysosomal system, including abnormally enlarged endosomal compartments, accumulation of protease-resistant proteins, and atypical activation of the lysosomal system. The functional mechanisms accounting for these abnormalities have not yet been delineated. Towards our goal of identifying the proteins whose dysfunction contributes to the development of endosomal/lysosomal pathology in AD, we have found that: 1) proteins implicated in regulating late endosomal trafficking are among the targets of oxidation (carbonylation) in the brain of a presenilin 1/amyloid precursor protein (PS1/APP) transgenic mouse model of AD; 2) reduced neuronal expression of synaptic membrane protein HNK-1/NCAM is associated with Aß pathology in models of Aß deposition in cell culture and an amyloid precursor protein (APP) transgenic mouse, and is a potential consequence of impaired endosomal sorting of proteins that are trafficked to synaptic terminals under non-pathological conditions; and 3) perturbation of the function of vacuolar protein sorting protein 4b (Vps4b) in regulating multivesicular body (MVB) biogenesis and endosomal trafficking results in its abnormal association with proteins involved in cell death and protein turnover.; Our functional proteomic approach relies upon the specific isolation of sub-proteomes, or protein interaction modules, that are assembled in a sub-cellular location- and stimulus-specific manner to carry out distinct cellular tasks. The physical association of the components of these protein interaction modules results in the causation of a particular phenotype that may or may not have a role in disease pathogenesis depending upon the post-translational modification, sub-cellular localization, and relative abundances of the protein interaction module constituents. We have applied sensitive mass spectrometry techniques and robust computational biology methods to the qualitative and quantitative anaylsis of protein interaction modules that are potentially involved in the causation of the endosomal/lysosomal abnormalities associated with neurodegeneration in AD using various cell culture and transgenic mouse models of AD pathogenesis. |
| Keyword | Vps4b; HNK-1/NCAM; LC-MS/MS; proteomics; amyloid beta; Alzheimer's disease |
| 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-m333 |
| Contributing entity | University of Southern California |
| Rights | Thomas, Stefani Nicole Cottrell |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Thomas-20070328 |
| Archival file | uscthesesreloadpub_Volume17/etd-Thomas-20070328.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | FUNCTIONAL PROTEOMIC ANALYSIS OF ALTERED PROTEIN SIGNALING MODULES IN ALZHEIMER’S DISEASE by Stefani Nicole Cottrell Thomas 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 (PHARMACEUTICAL SCIENCES) May 2007 Copyright 2007 Stefani Nicole Cottrell Thomas |
