Combined analysis of the glia secretome and the CSF proteome: Neuroinflammation and novel biomarkers

Expert Review of Proteomics

Volumn 7, Issue 2, 2010, Pages 263-274

  Suk, Kyoungho ^a  

^a Kyungpook National University School of Medicine   (South Korea)

Author keywords

Biomarker; Cerebrospinal fluid; CNS; Glia; Neurodegenerative disease; Neuroinflammation; Omics; Proteome; Secretome; Systems biology

Indexed keywords

BIOLOGICAL MARKER; PROTEIN; PROTEOME; SECRETOME; UNCLASSIFIED DRUG;

ASTROCYTE; BRAIN NERVE CELL; CELL COMMUNICATION; CELL INTERACTION; CENTRAL NERVOUS SYSTEM; CEREBROSPINAL FLUID; COMPARATIVE STUDY; COMPREHENSION; CYTOLOGY; DEGENERATIVE DISEASE; ENCEPHALITIS; GLIA; GLIA CELL; HUMAN; KNOWLEDGE; MICROGLIA; NONHUMAN; PATHOLOGY; PHYSIOLOGY; PROTEIN ANALYSIS; PROTEIN CEREBROSPINAL FLUID LEVEL; PROTEIN SECRETION; PROTEOMICS; REVIEW;

ANIMALS; BIOLOGICAL MARKERS; CENTRAL NERVOUS SYSTEM DISEASES; CEREBROSPINAL FLUID PROTEINS; HUMANS; MODELS, BIOLOGICAL; NEUROGLIA; PROTEOME;

EID: 77950847889     PISSN: 14789450     EISSN: 17448387     Source Type: Journal    
DOI: 10.1586/epr.10.6     Document Type: Review

References (116)

1. Streit WJ, Mrak RE, Griffin WS. Microglia and neuroinflammation: a pathological perspective. J. Neuroinflammation 1(1), 14 (2004).
2. Harry GJ, Kraft AD. Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment. Expert Opin. Drug Metab. Toxicol. 4(10), 1265-1277 (2008).
3. Graeber MB, Streit WJ. Microglia: biology and pathology. Acta Neuropathol. 119(1), 89-105 (2010).
4. Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119-145 (2009).
5. Pivneva TA. Microglia in normal condition and pathology. Fiziol. Zh. 54(5), 81-89 (2008).
6. Lynch MA. The multifaceted profile of activated microglia. Mol. Neurobiol. 40(2), 139-156 (2009).
7. Seth P, Koul N. Astrocyte, the star avatar: redefined. J. Biosci. 33(3), 405-421 (2008).
8. Wang DD, Bordey A. The astrocyte odyssey. Prog. Neurobiol. 86(4), 342-367 (2008).
9. Araque A, Perea G. Glial modulation of synaptic transmission in culture. Glia 47(3), 241-248 (2004). (Pubitemid 39121069)
10. Norton WT, Aquino DA, Hozumi I, Chiu FC, Brosnan CF. Quantitative aspects of reactive gliosis: a review. Neurochem. Res. 17(9), 877-885 (1992).
11. Kim SU, de Vellis J. Microglia in health and disease. J. Neurosci. Res. 81(3), 302-313 (2005). (Pubitemid 41359284)
12. Walter L, Neumann H. Role of microglia in neuronal degeneration and regeneration. Semin. Immunopathol. 31(4), 513-525.
13. Sanders P, De Keyser J. Janus faces of microglia in multiple sclerosis. Brain Res. Rev. 54(2), 274-285 (2007). (Pubitemid 46891077)
14. Nakajima K, Kohsaka S. Microglia: activation and their significance in the central nervous system. J. Biochem. (Tokyo) 130(2), 169-175 (2001). (Pubitemid 32785862)
15. Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J. Pharmacol. Exp. Ther. 304(1), 1-7 (2003). (Pubitemid 36008905)
16. Chavarria A, Alcocer-Varela J. Is damage in central nervous system due to inflammation? Autoimmun. Rev. 3(4), 251-260 (2004). (Pubitemid 38887620)
17. Olson EE, McKeon RJ. Characterization of cellular and neurological damage following unilateral hypoxia/ischemia. J. Neurol. Sci. 227(1), 7-19 (2004).
18. Morioka T, Kalehua AN, Streit WJ. Characterization of microglial reaction after middle cerebral artery occlusion in rat brain. J. Comp. Neurol. 327(1), 123-132 (1993). (Pubitemid 23006616)
19. Inoue K, Tsuda M. Microglia and neuropathic pain. Glia 57(14), 1469-1479 (2009).
20. Akiyama H, Barger S, Barnum S et al. Inflammation and Alzheimer's disease. Neurobiol. Aging 21(3), 383-421 (2000). (Pubitemid 30349107)
21. El Khoury J, Luster AD. Mechanisms of microglia accumulation in Alzheimer's disease: therapeutic implications. Trends Pharmacol. Sci. 29(12), 626-632 (2008).
22. Forman MS, Trojanowski JQ, Lee VM. Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat. Med. 10(10), 1055-1063 (2004).
23. Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A. Neuroinflammation in Alzheimer's disease and Parkinson's disease: are microglia pathogenic in either disorder? Int. Rev. Neurobiol. 82, 235-246 (2007).
24. Kim YS, Joh TH. Microglia major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease. Exp. Mol. Med. 38(4), 333-347 (2006). (Pubitemid 44351428)
25. Long-Smith CM, Sullivan AM, Nolan YM. The influence of microglia on the pathogenesis of Parkinson's disease. Prog. Neurobiol. 89(3), 277-287 (2009).
26. Villoslada P, Steinman L, Baranzini SE. Systems biology and its application to the understanding of neurological diseases. Ann. Neurol. 65(2), 124-139 (2009).
27. Geschwind DH, Konopka G. Neuroscience in the era of functional genomics and systems biology. Nature 461(7266), 908-915 (2009).
28. Quintana FJ, Farez MF, Weiner HL. Systems biology approaches for the study of multiple sclerosis. J. Cell Mol. Med. 12(4), 1087-1093 (2008).
29. Vodovotz Y, Csete M, Bartels J, Chang S, An G. Translational systems biology of inflammation. PLoS Comput. Biol. 4(4), e1000014 (2008).
30. Grant SG. Systems biology in neuroscience: bridging genes to cognition. Curr. Opin. Neurobiol. 13(5), 577-582 (2003).
31. Hwang D, Lee IY, Yoo H et al. A systems approach to prion disease. Mol. Syst. Biol. 5, 252 (2009).
32. Kandpal R, Saviola B, Felton J. The era of 'omics unlimited. Biotechniques 46(5), 351-352, 354-355 (2009).
33. Bruggeman FJ, Westerhoff HV. The nature of systems biology. Trends Microbiol. 15(1), 45-50 (2007).
34. Kitano H. Systems biology: a brief overview. Science 295(5560), 1662-1664 (2002). (Pubitemid 34202893)
35. Kirschner MW. The meaning of systems biology. Cell 121(4), 503-504 (2005).
36. Aderem A. Systems biology: its practice and challenges. Cell 121(4), 511-513 (2005). (Pubitemid 40720005)
37. Liu ET. Systems biology, integrative biology, predictive biology. Cell 121(4), 505-506 (2005).
38. Petranovic D, Nielsen J. Can yeast systems biology contribute to the understanding of human disease? Trends Biotechnol. 26(11), 584-590 (2008).
39. Hathout Y. Approaches to the study of the cell secretome. Expert Rev. Proteomics 4(2), 239-248 (2007). (Pubitemid 46588459)
40. Weston AD, Hood L. Systems biology, proteomics and the future of health care: toward predictive, preventative, and personalized medicine. J. Proteome Res. 3(2), 179-196 (2004). (Pubitemid 38500984)
41. Greenbaum D, Luscombe NM, Jansen R, Qian J, Gerstein M. Interrelating different types of genomic data, from proteome to secretome: 'oming in on function. Genome Res. 11(9), 1463-1468 (2001). (Pubitemid 32894671)
42. Grimmond SM, Miranda KC, Yuan Z et al. The mouse secretome: functional classification of the proteins secreted into the extracellular environment. Genome Res. 13(6B), 1350-1359 (2003). (Pubitemid 36827231)
43. Thouvenot E, Lafon-Cazal M, Demettre E, Jouin P, Bockaert J, Marin P. The proteomic analysis of mouse choroid plexus secretome reveals a high protein secretion capacity of choroidal epithelial cells. Proteomics 6(22), 5941-5952 (2006). (Pubitemid 44851380)
44. Khwaja FW, Svoboda P, Reed M, Pohl J, Pyrzynska B, Van Meir EG. Proteomic identification of the wt-p53-regulated tumor cell secretome. Oncogene 25(58), 7650-7661 (2006). (Pubitemid 44924478)
45. Pellitteri-Hahn MC, Warren MC, Didier DN et al. Improved mass spectrometric proteomic profiling of the secretome of rat vascular endothelial cells. J. Proteome Res. 5(10), 2861-2864 (2006).
46. Zvonic S, Lefevre M, Kilroy G et al. Secretome of primary cultures of human adipose-derived stem cells: modulation of serpins by adipogenesis. Mol. Cell Proteomics 6(1), 18-28 (2007). (Pubitemid 46152688)
47. Dupont A, Corseaux D, Dekeyzer O et al. The proteome and secretome of human arterial smooth muscle cells. Proteomics 5(2), 585-596 (2005). (Pubitemid 40262075)
48. Dupont A, Tokarski C, Dekeyzer O et al. Two-dimensional maps and databases of the human macrophage proteome and secretome. Proteomics 4(6), 1761-1778 (2004). (Pubitemid 38738331)
49. Lafon-Cazal M, Adjali O, Galeotti N et al. Proteomic analysis of astrocytic secretion in the mouse. Comparison with the cerebrospinal fluid proteome. J. Biol. Chem. 278(27), 24438-24448 (2003). (Pubitemid 37548595)
50. Delcourt N, Jouin P, Poncet J et al. Difference in mass analysis using labeled lysines (DIMAL-K): a new, efficient proteomic quantification method applied to the analysis of astrocytic secretomes. Mol. Cell Proteomics 4(8), 1085-1094 (2005). (Pubitemid 41223368)
51. Wu HY, Chang YH, Chang YC, Liao PC. Proteomics analysis of nasopharyngeal carcinoma cell secretome using a hollow fiber culture system and mass spectrometry. J. Proteome Res. 8(1), 380-389 (2009).
52. Dowell JA, Johnson JA, Li L. Identification of astrocyte secreted proteins with a combination of shotgun proteomics and bioinformatics. J. Proteome Res. 8(8), 4135-4143 (2009).
53. Keene SD, Greco TM, Parastatidis I et al. Mass spectrometric and computational analysis of cytokine-induced alterations in the astrocyte secretome. Proteomics 9(3), 768-782 (2009).
54. Kim S, Ock J, Kim AK et al. Neurotoxicity of microglial cathepsin D revealed by secretome analysis. J. Neurochem. 103(6), 2640-2650 (2007).
55. Liu J, Hong Z, Ding J, Liu J, Zhang J, Chen S. Predominant release of lysosomal enzymes by newborn rat microglia after LPS treatment revealed by proteomic studies. J. Proteome Res. 7(5), 2033-2049 (2008).
56. Mohri I, Taniike M, Taniguchi H et al. Prostaglandin D2-mediated microglia/ astrocyte interaction enhances astrogliosis and demyelination in twitcher. J. Neurosci. 26(16), 4383-4393 (2006). (Pubitemid 44315397)
57. Hansson E, Ronnback L. Glial neuronal signaling in the central nervous system. FASEB J. 17(3), 341-348 (2003). (Pubitemid 36292950)
58. Biber K, Vinet J, Boddeke HW. Neuron-microglia signaling: chemokines as versatile messengers. J. Neuroimmunol. 198(1-2), 69-74 (2008).
59. Wang T, Gong N, Liu J et al. HIV-1- infected astrocytes and the microglial proteome. J. Neuroimmune Pharmacol. 3(3), 173-186 (2008).
60. Rohl C, Armbrust E, Kolbe K et al. Activated microglia modulate astroglial enzymes involved in oxidative and inflammatory stress and increase the resistance of astrocytes to oxidative stress in vitro. Glia 56(10), 1114-1126 (2008).
61. Tannu NS, Hemby SE. Methods for proteomics in neuroscience. Prog. Brain Res. 158, 41-82 (2006).
62. Poon TC. Opportunities and limitations of SELDI-TOF-MS in biomedical research: practical advices. Expert Rev. Proteomics 4(1), 51-65 (2007).
63. Seibert V, Ebert MP, Buschmann T. Advances in clinical cancer proteomics: SELDI-ToF-mass spectrometry and biomarker discovery. Brief. Funct. Genomic Proteomic 4(1), 16-26 (2005). (Pubitemid 40724164)
64. Findeisen P, Neumaier M. Mass spectrometry-based clinical proteomics profiling: current status and future directions. Expert Rev. Proteomics 6(5), 457-459 (2009).
65. Xue H, Lu B, Lai M. The cancer secretome: a reservoir of biomarkers. J. Transl. Med. 6, 52 (2008).
66. Zwickl H, Traxler E, Staettner S et al. A novel technique to specifically analyze the secretome of cells and tissues. Electrophoresis 26(14), 2779-2785 (2005). (Pubitemid 41078987)
67. Enose Y, Destache CJ, Mack AL et al. Proteomic fingerprints distinguish microglia bone marrow, and spleen macrophage populations. Glia 51(3), 161-172 (2005). (Pubitemid 41297423)
68. Potolicchio I, Carven GJ, Xu X et al. Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J. Immunol. 175(4), 2237-2243 (2005). (Pubitemid 41113830)
69. Reynolds AD, Stone DK, Mosley RL, Gendelman HE. Proteomic studies of nitrated a-synuclein microglia regulation by CD4+CD25+ T cells. J. Proteome Res. 8(7), 3497-3511 (2009).
70. Bernhart E, Kollroser M, Rechberger G et al. Lysophosphatidic acid receptor activation affects the C13NJ microglial cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture. Proteomics 10(1), 141-158 (2010).
71. Egnaczyk GF, Pomonis JD, Schmidt JA et al. Proteomic analysis of the reactive phenotype of astrocytes following endothelin-1 exposure. Proteomics 3(5), 689-698 (2003).
72. Yang JW, Suder P, Silberring J, Lubec G. Proteome analysis of mouse primary astrocytes. Neurochem. Int. 47(3), 159-172 (2005). (Pubitemid 40848678)
73. Hauck SM, Suppmann S, Ueffing M. Proteomic profiling of primary retinal Muller glial cells reveals a shift in expression patterns upon adaptation to in vitro conditions. Glia 44(3), 251-263 (2003). (Pubitemid 37484476)
74. Pocernich CB, Boyd-Kimball D, Poon HF et al. Proteomics analysis of human astrocytes expressing the HIV protein Tat. Brain Res. Mol. Brain Res. 133(2), 307-316 (2005). (Pubitemid 40248421)
75. Moore NH, Costa LG, Shaffer SA, Goodlett DR, Guizzetti M. Shotgun proteomics implicates extracellular matrix proteins and protease systems in neuronal development induced by astrocyte cholinergic stimulation. J. Neurochem. 108(4), 891-908 (2009).
76. Thouvenot E, Urbach S, Dantec C et al. Enhanced detection of CNS cell secretome in plasma protein-depleted cerebrospinal fluid. J. Proteome Res. 7(10), 4409-4421 (2008).
77. Bachoo RM, Kim RS, Ligon KL et al. Molecular diversity of astrocytes with implications for neurological disorders. Proc. Natl Acad. Sci. USA 101(22), 8384-8389 (2004).
78. Cahoy JD, Emery B, Kaushal A et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28(1), 264-278 (2008).
79. Gabelle A, Roche S, Lehmann S. [CSF biomarkers: proteomics investigations and clinical applications in neurodegenerative disorders]. Rev. Neurol. (Paris) 165(3), 213-222 (2009).
80. Maurer MH. Proteomics of brain extracellular fluid (ECF) and cerebrospinal fluid (CSF). Mass Spectrom. Rev. 29(1), 17-28 (2010).
81. Westman-Brinkmalm A, Ruetschi U, Portelius E et al. Proteomics/ peptidomics tools to find CSF biomarkers for neurodegenerative diseases. Front. Biosci. 14, 1793 - 1806 (2009).
82. Zougman A, Pilch B, Podtelejnikov A et al. Integrated analysis of the cerebrospinal fluid peptidome and proteome. J. Proteome Res. 7(1), 386-399 (2008). (Pubitemid 351171153)
83. Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N. Engl. J. Med. 348(14), 1356-1364 (2003).
84. Teunissen CE, Petzold A, Bennett JL et al. A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 73(22), 1914-1922 (2009).
85. Tumani H, Teunissen C, Sussmuth S, Otto M, Ludolph AC, Brettschneider J. Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases. Expert Rev. Mol. Diagn. 8(4), 479-494 (2008). (Pubitemid 351962092)
86. Romeo MJ, Espina V, Lowenthal M, Espina BH, Petricoin EF 3rd, Liotta LA. CSF proteome: a protein repository for potential biomarker identification. Expert Rev. Proteomics 2(1), 57-70 (2005). (Pubitemid 40292580)
87. Davidsson P, Sjogren M. Proteome studies of CSF in AD patients. Mech. Ageing Dev. 127(2), 133-137 (2006). (Pubitemid 43165612)
88. Ekegren T, Hanrieder J, Bergquist J. Clinical perspectives of high-resolution mass spectrometry-based proteomics in neuroscience: exemplified in amyotrophic lateral sclerosis biomarker discovery research. J. Mass Spectrom. 43(5), 559-571 (2008). (Pubitemid 351785680)
89. Pan S, Zhu D, Quinn JF et al. A combined dataset of human cerebrospinal fluid proteins identified by multi-dimensional chromatography and tandem mass spectrometry. Proteomics 7(3), 469-473 (2007). (Pubitemid 46293989)
90. Zhang J, Goodlett DR, Montine TJ. Proteomic biomarker discovery in cerebrospinal fluid for neurodegenerative diseases. J. Alzheimers Dis. 8(4), 377-386 (2005).
91. Aluise CD, Sowell RA, Butterfield DA. Peptides and proteins in plasma and cerebrospinal fluid as biomarkers for the prediction, diagnosis, and monitoring of therapeutic efficacy of Alzheimer's disease. Biochim. Biophys. Acta 1782(10), 549-558 (2008).
92. Shaw LM, Vanderstichele H, Knapik- Czajka M et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann. Neurol. 65(4), 403-413 (2009).
93. Yin GN, Lee HW, Cho JY, Suk K. Neuronal pentraxin receptor in cerebrospinal fluid as a potential biomarker for neurodegenerative diseases. Brain Res. 1265, 158-170 (2009).
94. Zhang J, Goodlett DR, Quinn JF et al. Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer disease. J. Alzheimers Dis. 7(2), 125-133; discussion 173-180 (2005). (Pubitemid 40592186)
95. Straten G, Eschweiler GW, Maetzler W, Laske C, Leyhe T. Glial cell-line derived neurotrophic factor (GDNF) concentrations in cerebrospinal fluid and serum of patients with early Alzheimer's disease and normal controls. J. Alzheimers Dis. 18(2), 331-337 (2009).
96. Jesse S, Steinacker P, Cepek L et al. Glial fibrillary acidic protein and protein S-100B: different concentration pattern of glial proteins in cerebrospinal fluid of patients with Alzheimer's disease and Creutzfeldt-Jakob disease. J. Alzheimers Dis. 17(3), 541-551 (2009).
97. Eller M, Williams DR. Biological fluid biomarkers in neurodegenerative parkinsonism. Nat. Rev. Neurol. 5(10), 561-570 (2009).
98. Abdi F, Quinn JF, Jankovic J et al. Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders. J. Alzheimers Dis. 9(3), 293-348 (2006). (Pubitemid 44253348)
99. Constantinescu R, Zetterberg H, Holmberg B, Rosengren L. Levels of brain related proteins in cerebrospinal fluid: an aid in the differential diagnosis of parkinsonian disorders. Parkinsonism Relat. Disord. 15(3), 205-212 (2009).
100. Mitchell RM, Freeman WM, Randazzo WT et al. A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis. Neurology 72(1), 14-19 (2009).
101. Brechlin P, Jahn O, Steinacker P et al. Cerebrospinal fluid-optimized two-dimensional difference gel electrophoresis (2-D DIGE) facilitates the differential diagnosis of Creutzfeldt-Jakob disease. Proteomics 8(20), 4357-4366 (2008).
102. Bayes A, Grant SG. Neuroproteomics: understanding the molecular organization and complexity of the brain. Nat. Rev. Neurosci. 10(9), 635-646 (2009).
103. Lewczuk P, Zimmermann R, Wiltfang J, Kornhuber J. Neurochemical dementia diagnostics: a simple algorithm for interpretation of the CSF biomarkers. J. Neural Transm. 116(9), 1163-1167 (2009).
104. Choi C, Jeong JH, Jang JS et al. Multiplex analysis of cytokines in the serum and cerebrospinal fluid of patients with Alzheimer's disease by color-coded bead technology. J. Clin. Neurol. 4(2), 84-88 (2008).
105. Ray S, Britschgi M, Herbert C et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat. Med. 13(11), 1359-1362 (2007). (Pubitemid 350073592)
106. Knopman DS, DeKosky ST, Cummings JL et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56(9), 1143-1153 (2001). (Pubitemid 32405708)
107. Cedazo-Minguez A, Winblad B. Biomarkers for Alzheimer's disease and other forms of dementia: clinical needs, limitations and future aspects. Exp. Gerontol. 45(1), 5-14 (2010).
108. Kunz GM Jr, Chan DW. The use of laser capture microscopy in proteomics research - a review. Dis. Markers 20(3), 155-160 (2004).
109. Ye X, Blonder J, Veenstra TD. Targeted proteomics for validation of biomarkers in clinical samples. Brief Funct. Genomic Proteomic 8(2), 126-135 (2009).
110. Yocum AK, Chinnaiyan AM. Current affairs in quantitative targeted proteomics: multiple reaction monitoring-mass spectrometry. Brief. Funct. Genomic Proteomic 8(2), 145-157 (2009).
111. Pan S, Aebersold R, Chen R et al. Mass spectrometry based targeted protein quantification: methods and applications. J. Proteome Res. 8(2), 787-797 (2009).
112. Anderson L, Hunter CL. Quantitative mass spectrometric multiple reaction monitoring assays for major plasma proteins. Mol. Cell Proteomics 5(4), 573-588 (2006).
113. Picotti P, Bodenmiller B, Mueller LN, Domon B, Aebersold R. Full dynamic range proteome analysis of S. cerevisiae by targeted proteomics. Cell 138(4), 795-806 (2009).
114. Pasinetti GM, Ungar LH, Lange DJ et al. Identification of potential CSF biomarkers in ALS. Neurology 66(8), 1218-1222 (2006).
115. O'Connor KC, Roy SM, Becker CH, Hafler DA, Kantor AB. Comprehensive phenotyping in multiple sclerosis: discovery based proteomics and the current understanding of putative biomarkers. Dis. Markers 22(4), 213-225 (2006).
116. Qin Z, Qin Y, Liu S. Alteration of DBP levels in CSF of patients with MS by proteomics analysis. Cell Mol. Neurobiol. 29(2), 203-210 (2009).