title: Using proteomics and network analysis to elucidate the consequences of synaptic protein oxidation in a PS1 + AbetaPP mouse model of Alzheimer's disease.
abstract: Increasing evidence suggests that oxidative injury is involved in the pathogenesis of many age-related neurodegenerative disorders, including Alzheimer's disease (AD). Identifying the protein targets of oxidative stress is critical to determine which proteins may be responsible for the neuronal impairments and subsequent cell death that occurs in AD. In this study, we have applied a high-throughput shotgun proteomic approach to identify the targets of protein carbonylation in both aged and PS1 + AbetaPP transgenic mice. However, because of the inherent difficulties associated with proteomic database searching algorithms, several newly developed bioinformatic tools were implemented to ascertain a probability-based discernment between correct protein assignments and false identifications to improve the accuracy of protein identification. Assigning a probability to each identified peptide/protein allows one to objectively monitor the expression and relative abundance of particular proteins from diverse samples, including tissue from transgenic mice of mixed genetic backgrounds. This robust bioinformatic approach also permits the comparison of proteomic data generated by different laboratories since it is instrument- and database-independent. Applying these statistical models to our initial studies, we detected a total of 117 oxidatively modified (carbonylated) proteins, 59 of which were specifically associated with PS1 + AbetaPP mice. Pathways and network component analyses suggest that there are three major protein networks that could be potentially altered in PS1 + AbetaPP mice as a result of oxidative modifications. These pathways are 1) iNOS-integrin signaling pathway, 2) CRE/CBP transcription regulation and 3) rab-lyst vesicular trafficking. We believe the results of these studies will help establish an initial AD database of oxidatively modified proteins and provide a foundation for the design of future hypothesis driven research in the areas of aging and neurodegeneration.
authors.affiliation: Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Soreghan
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Lu
authors.forename: Stefani N
authors.initials: SN
authors.lastname: Thomas
authors.forename: Karen
authors.initials: K
authors.lastname: Duff
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Rakhmatulin
authors.forename: Tatiana
authors.initials: T
authors.lastname: Nikolskaya
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Yang
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D016023:Integrins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009415:Nerve Net / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D053764:Presenilin-1; D011336:Probability; D050050:Protein Carbonylation / Q000502:physiology; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction / Q000502:physiology; D013570:Synaptic Membranes / Q000378:metabolism* / Q000473:pathology
chemical_list: D051698:Activating Transcription Factor 2; D016564:Amyloid beta-Protein Precursor; C497106:Atf2 protein, mouse; D016023:Integrins; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D053764:Presenilin-1; D019001:Nitric Oxide Synthase