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Protein Profiling Analysis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis Brain Tissue

Azzam, Sausan

Abstract Details

2011, PHD, Kent State University, College of Arts and Sciences / Department of Chemistry.

Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system. Although MS seems to be primarily an inflammatory autoimmune disease, it has become evident that axonal loss plays an important role in the pathogenesis of the disease. Mitochondrial dysfunction and oxidative damage have been implicated in the neuropathology associated with MS and other neurodegenerative diseases. Mitochondrial dysfunction may also play a role in disease pathology in the experimental allergic encephalomyelitis (EAE) mouse model of MS. Previous studies have demonstrated defects in mitochondrial electron transport gene expression in normal appearing gray matter (NAGM) in postmortem MS cortex. These studies have identified transcriptional changes in mitochondrial genes, yet translational or post-translational alterations of proteins may also impact mitochondrial function and energy production. To date, few studies have utilized proteomic approaches to investigate the differentially expressed proteins in the MS brain and its animal model.

Our lab has recently reported the identification of several mitochondrial proteins that are found to be altered in NAGM of MS as compared to control cortex. In the current study, we have applied several proteomic approaches to mitochondrial fractions derived from EAE and control mice to obtain a more complete understanding of protein expression changes that could contribute to the mechanisms of mitochondrial dysfunction in MS. In order to ascertain that the resulting variation reflects biological differences between diseased and control states, we first investigated the reproducibility of our cell fractionation techniques and Surface Enhanced Laser Desorption Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS) methodology. We then employed SELDI-TOF-MS to analyze MS and control postmortem brain tissue and the brains of EAE and control mice and we observed changes in a number of mitochondrial proteins, as well as increases in the levels of myelin basic protein (MBP) associated with mitochondrial fractions.

MBP is released into Cerebrospinal Fluid (CSF) and is found in the blood in MS patients. It has been shown to kill oligodendrocytes in cell culture. Therefore, in this study we further investigated the effect of MBP on other cell types (neurons and neuroblastoma cells). We have shown that MBP is taken up by neuroblastoma cells where it appears to be associated with mitochondria and leads to apoptosis. MBP also leads to a collapse of the mitochondrial membrane potential in neurons. Free MBP may therefore contribute directly to neurodegeneration in MS. These results may eventually lead to a better understanding of the mechanisms underlying the pathogenesis of MS.

Roger Gregory (Advisor)
Jenifer McDonough (Advisor)
Frederick Walz (Committee Member)
Arne Gericke (Committee Member)
Ernest Freeman (Committee Member)
Robert Dorman (Committee Member)
216 p.

Recommended Citations

Citations

  • Azzam, S. (2011). Protein Profiling Analysis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis Brain Tissue [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1302472724

    APA Style (7th edition)

  • Azzam, Sausan. Protein Profiling Analysis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis Brain Tissue. 2011. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1302472724.

    MLA Style (8th edition)

  • Azzam, Sausan. "Protein Profiling Analysis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis Brain Tissue." Doctoral dissertation, Kent State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=kent1302472724

    Chicago Manual of Style (17th edition)