The ubiquitin-proteasome system is the major intracellular molecular machinery for protein degradation and maintenance of protein homeostasis in most human cells. As ubiquitin-proteasome system plays a critical role in the regulation of the immune system, it might also influence the development and progression of multiple sclerosis (MS). Both ex vivo analyses and animal models suggest that activity and composition of ubiquitin-proteasome system are altered in MS. Proteasome isoforms endowed of immunosubunits may affect the functionality of different cell types such as CD8+ and CD4+ T cells and B cells as well as neurons during MS development. Furthermore, the study of proteasome-related biomarkers, such as proteasome antibodies and circulating proteasomes, may represent a field of interest in MS. Proteasome inhibitors are already used as treatment for cancer and the recent development of inhibitors selective for immunoproteasome subunits may soon represent novel therapeutic approaches to the different forms of MS. In this review we describe the current knowledge on the potential role of proteasomes in MS and discuss the pro et contra of possible therapies for MS targeting proteasome isoforms. 1. Multiple Sclerosis and Proteasome Isoforms Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by the presence of inflammation, myelin damage, and axonal degeneration. There are two main clinical courses of multiple sclerosis: about 90% of MS patients experience the relapsing-remitting MS phase (RRMS), characterized by disability episodes followed by a complete or partial recovery. Multifocal lesions are found by magnetic resonance imaging, typically but not exclusively, in the white matter of the optic nerve, brain stem, cerebellum, and spinal cord. Some lesions are enhanced after intravenous administration of gadolinium, indicating breakdown of the blood-brain barrier (BBB) as a result of active inflammation. The majority of RRMS patients enter into a secondary progressive phase (SPMS), characterized by a variable degree of inflammation and a continuous and progressive neurological decline in disability state (with or without superimposed relapses) [1, 2]. A minor percentage (10%) of MS patients shows a primary progressive form of MS (PPMS), characterized by progression of neurological disability from onset. Clinically relevant factors differentiating RRMS and PPMS are age at disease onset (a decade later in PPMS) and gender (1？:？1.3 male/female in PPMS versus 1？:？2 in RRMS) [3]. Although the initial course of RRMS
References
[1]
E. M. Frohman, M. K. Racke, and C. S. Raine, “Multiple sclerosis. The plaque and its pathogenesis,” The New England Journal of Medicine, vol. 354, no. 9, pp. 942–955, 2006.
[2]
P. K. Stys, G. W. Zamponi, J. van Minnen, and J. J. Geurts, “Will the real multiple sclerosis please stand up?” Nature Reviews Neuroscience, vol. 13, no. 7, pp. 507–514, 2012.
[3]
A. Compston and A. Coles, “Multiple sclerosis,” The Lancet, vol. 372, no. 9648, pp. 1502–1517, 2008.
[4]
G. Giovannoni and G. Ebers, “Multiple sclerosis: the environment and causation,” Current Opinion in Neurology, vol. 20, no. 3, pp. 261–268, 2007.
[5]
S. Jilek, M. Schluep, A. Harari et al., “HLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in multiple sclerosis,” Journal of Immunology, vol. 188, no. 9, pp. 4671–4680, 2012.
[6]
L. Fugger, M. A. Friese, and J. I. Bell, “From genes to function: the next challenge to understanding multiple sclerosis,” Nature Reviews Immunology, vol. 9, no. 6, pp. 408–417, 2009.
[7]
B. D. Trapp and K.-A. Nave, “Multiple sclerosis: an immune or neurodegenerative disorder?” Annual Review of Neuroscience, vol. 31, pp. 247–269, 2008.
[8]
A. L. Goldberg, “Functions of the proteasome: from protein degradation and immune surveillance to cancer therapy,” Biochemical Society Transactions, vol. 35, no. 1, pp. 12–17, 2007.
[9]
B. Dahlmann, “Role of proteasomes in disease,” BMC Biochemistry, vol. 8, no. 1, article S3, 2007.
[10]
F. Schmidt, B. Dahlmann, H. K. Hustoft et al., “Quantitative proteome analysis of the 20S proteasome of apoptotic Jurkat T cells,” Amino Acids, vol. 41, no. 2, pp. 351–361, 2011.
[11]
F. Ebstein, P.-M. Kloetzel, E. Krüger, and U. Seifert, “Emerging roles of immunoproteasomes beyond MHC class I antigen processing,” Cellular and Molecular Life Sciences, vol. 69, no. 15, pp. 2543–2558, 2012.
[12]
A. M. Weissman, N. Shabek, and A. Ciechanover, “The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation,” Nature Reviews Molecular Cell Biology, vol. 12, no. 9, pp. 605–620, 2011.
[13]
M. Bochtler, L. Ditzel, M. Groll, C. Hartmann, and R. Huber, “The proteasome,” Annual Review of Biophysics and Biomolecular Structure, vol. 28, pp. 295–317, 1999.
[14]
D. Voges, P. Zwickl, and W. Baumeister, “The 26S proteasome: a molecular machine designed for controlled proteolysis,” Annual Review of Biochemistry, vol. 68, pp. 1015–1068, 1999.
[15]
C. Pintado, M. P. Gavilán, E. Gavilán et al., “Lipopolysaccharide-induced neuroinflammation leads to the accumulation of ubiquitinated proteins and increases susceptibility to neurodegeneration induced by proteasome inhibition in rat hippocampus,” Journal of Neuroinflammation, vol. 9, no. 1, article 87, 2012.
[16]
D. A. Ferrington and D. S. Gregerson, “Immunoproteasomes: structure, function, and antigen presentation,” Progress in Molecular Biology and Translational Science, vol. 109, pp. 75–112, 2012.
[17]
N. Qureshi, D. C. Morrison, and J. Reis, “Proteasome protease mediated regulation of cytokine induction and inflammation,” Biochimica et Biophysica Acta, vol. 1823, no. 11, pp. 2087–2093, 2012.
[18]
J. Zheng and O. A. Bizzozero, “Decreased activity of the 20S proteasome in the brain white matter and gray matter of patients with multiple schlerosis,” Journal of Neurochemistry, vol. 117, no. 1, pp. 143–153, 2011.
[19]
M. Orre, W. Kamphuis, S. Dooves et al., “Reactive glia show increased immunoproteasome activity in Alzheimer's disease,” Brain, vol. 136, no. 5, pp. 1415–1431, 2013.
[20]
S. Gohlke, M. Mishto, K. Textoris-Taube et al., “Molecular alterations in proteasomes of rat liver during aging result in altered proteolytic activities,” Age, 2013.
[21]
C. Giannini, A. Kloss, S. Gohlke et al., “Poly-ub-substrate-degradative activity of 26S proteasome is not impaired in the aging rat brain,” PLoS ONE, vol. 8, no. 5, Article ID e64042, 2013.
[22]
M. Mishto, E. Bellavista, C. Ligorio et al., “Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population,” PLoS ONE, vol. 5, no. 2, Article ID e9287, 2010.
[23]
J. Zheng, A. Dasgupta, and O. A. Bizzozero, “Changes in 20S subunit composition are largely responsible for altered proteasomal activities in experimental autoimmune encephalomyelitis,” Journal of Neurochemistry, vol. 121, no. 3, pp. 486–494, 2012.
[24]
M. Mishto, C. Ligorio, E. Bellavista et al., “Immunoproteasome expression is induced in mesial temporal lobe epilepsy,” Biochemical and Biophysical Research Communications, vol. 408, no. 1, pp. 65–70, 2011.
[25]
M. Kremer, A. Henn, C. Kolb et al., “Reduced immunoproteasome formation and accumulation of immunoproteasomal precursors in the brains of lymphocytic choriomeningitis virus-infected mice,” Journal of Immunology, vol. 185, no. 9, pp. 5549–5560, 2010.
[26]
M. P. Gavilán, A. Casta？o, M. Torres et al., “Age-related increase in the immunoproteasome content in rat hippocampus: molecular and functional aspects,” Journal of Neurochemistry, vol. 108, no. 1, pp. 260–272, 2009.
[27]
M. Mishto, E. Bellavista, A. Santoro et al., “Immunoproteasome and LMP2 polymorphism in aged and Alzheimer's disease brains,” Neurobiology of Aging, vol. 27, no. 1, pp. 54–66, 2006.
[28]
E. Bellavista, M. Mishto, A. Santoro, C. Bertoni-Freddari, R. B. Sessions, and C. Franceschi, “Immunoproteasome in Macaca fascicularis: no age-dependent modification of abundance and activity in the brain and insight into an in silico structural model,” Rejuvenation Research, vol. 11, no. 1, pp. 73–82, 2008.
[29]
M. Groettrup, C. J. Kirk, and M. Basler, “Proteasomes in immune cells: more than peptide producers?” Nature Reviews Immunology, vol. 10, no. 1, pp. 73–78, 2010.
[30]
S. A. Hussong, R. J. Kapphahn, S. L. Phillips, M. Maldonado, and D. A. Ferrington, “Immunoproteasome deficiency alters retinal proteasome's response to stress,” Journal of Neurochemistry, vol. 113, no. 6, pp. 1481–1490, 2010.
[31]
U. Seifert, L. P. Bialy, F. Ebstein et al., “Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress,” Cell, vol. 142, no. 4, pp. 613–624, 2010.
[32]
J. A. Nathan, V. Spinnenhirn, G. Schmidtke, M. Basler, M. Groettrup, and A. L. Goldberg, “Immuno- and constitutive proteasomes do not differ in their abilities to degrade ubiquitinated proteins,” Cell, vol. 152, no. 5, pp. 1184–1194.
[33]
M. A. Friese and L. Fugger, “Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy?” Brain, vol. 128, no. 8, pp. 1747–1763, 2005.
[34]
H. Yokote, S. Miyake, J. L. Croxford, S. Oki, H. Mizusawa, and T. Yamamura, “NKT cell-dependent amelioration of a mouse model of multiple sclerosis by altering gut flora,” The American Journal of Pathology, vol. 173, no. 6, pp. 1714–1723, 2008.
[35]
T. Tsuchida, K. C. Parker, R. V. Turner, H. F. McFarland, J. E. Coligan, and W. E. Biddison, “Autoreactive CD8+ T-cell responses to human myelin protein-derived peptides,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 23, pp. 10859–10863, 1994.
[36]
A. Jurewicz, W. E. Biddison, and J. P. Antel, “MHC class I-restricted lysis of human oligodendrocytes by myelin basic protein peptide-specific CD8 T lymphocytes,” Journal of Immunology, vol. 160, no. 6, pp. 3056–3059, 1998.
[37]
Y. C. Q. Zang, S. Li, V. M. Rivera et al., “Increased CD8+ cytotoxic T cell responses to myelin basic protein in multiple sclerosis,” Journal of Immunology, vol. 172, no. 8, pp. 5120–5127, 2004.
[38]
D. M. W. Zaiss, C. P. J. Bekker, A. Gr？ne, B. A. Lie, and A. J. A. M. Sijts, “Proteasome immunosubunits protect against the development of CD8 T cell-mediated autoimmune diseases,” Journal of Immunology, vol. 187, no. 5, pp. 2302–2309, 2011.
[39]
J. D. Lünemann, N. Edwards, P. A. Muraro et al., “Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis,” Brain, vol. 129, no. 6, pp. 1493–1506, 2006.
[40]
S. Jilek, M. Schluep, P. Meylan et al., “Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis,” Brain, vol. 131, no. 7, pp. 1712–1721, 2008.
[41]
P. H？llsberg, H. J. Hansen, and S. Haahr, “Altered CD8+ T cell responses to selected Epstein-Barr virus immunodominant epitopes in patients with multiple sclerosis,” Clinical and Experimental Immunology, vol. 132, no. 1, pp. 137–143, 2003.
[42]
S. Cepok, D. Zhou, R. Srivastava et al., “Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis,” Journal of Clinical Investigation, vol. 115, no. 5, pp. 1352–1360, 2005.
[43]
J. Ishizuka, K. Grebe, E. Shenderov et al., “Quantitating T cell cross-reactivity for unrelated peptide antigens,” Journal of Immunology, vol. 183, no. 7, pp. 4337–4345, 2009.
[44]
N. Vigneron, V. Stroobant, J. Chapiro et al., “An antigenic peptide produced by peptide splicing in the proteasome,” Science, vol. 304, no. 5670, pp. 587–590, 2004.
[45]
A. Dalet, N. Vigneron, V. Stroobant, K.-I. Hanada, and B. J. Van Den Eynde, “Splicing of distant peptide fragments occurs in the proteasome by transpeptidation and produces the spliced antigenic peptide derived from fibroblast growth factor-5,” Journal of Immunology, vol. 184, no. 6, pp. 3016–3024, 2010.
[46]
J. Liepe, M. Mishto, K. Textoris-Taube et al., “The 20S proteasome splicing activity discovered by SpliceMet,” PLoS Computational Biology, vol. 6, no. 6, Article ID e1000830, 2010.
[47]
M. Mishto, A. Goede, K. T. Taube et al., “Driving forces of proteasome-catalyzed peptide splicing in yeast and humans,” Molecular and Cellular Proteomics, vol. 11, no. 10, pp. 1008–1023, 2012.
K. Mori, M. Itoi, N. Tsukamoto, H. Kubo, and T. Amagai, “The perivascular space as a path of hematopoietic progenitor cells and mature T cells between the blood circulation and the thymic parenchyma,” International Immunology, vol. 19, no. 6, pp. 745–753, 2007.
[50]
E. Bettelli, Y. Carrier, W. Gao et al., “Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells,” Nature, vol. 441, no. 7090, pp. 235–238, 2006.
[51]
M. S. Maddur, P. Miossec, S. V. Kaveri, and J. Bayry, “Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies,” The American Journal of Pathology, vol. 181, no. 1, pp. 8–18, 2012.
[52]
J. S. Tzartos, M. A. Friese, M. J. Craner et al., “Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis,” The American Journal of Pathology, vol. 172, no. 1, pp. 146–155, 2008.
[53]
T. Carlson, M. Kroenke, P. Rao, T. E. Lane, and B. Segal, “The Th17-ELR+ CXC chemokine pathway is essential for the development of central nervous system autoimmune disease,” Journal of Experimental Medicine, vol. 205, no. 4, pp. 811–823, 2008.
[54]
V. Siffrin, H. Radbruch, R. Glumm et al., “In Vivo imaging of partially reversible Th17 cell-induced neuronal dysfunction in the course of encephalomyelitis,” Immunity, vol. 33, no. 3, pp. 424–436, 2010.
[55]
Y. Komiyama, S. Nakae, T. Matsuki et al., “IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 177, no. 1, pp. 566–573, 2006.
[56]
L. Cosmi, L. Maggi, V. Santarlasci et al., “Identification of a novel subset of human circulating memory CD4+ T cells that produce both IL-17A and IL-4,” Journal of Allergy and Clinical Immunology, vol. 125, no. 1–3, pp. 222-30.e1–222-30.e4, 2010.
[57]
K. Berer and G. Krishnamoorthy, “Commensal gut flora and brain autoimmunity: a love or hate affair?” Acta Neuropathologica, vol. 123, no. 5, pp. 639–651, 2012.
[58]
J. Bienenstock and S. Collins, “99th Dahlem Conference on Infection, Inflammation and Chronic Inflammatory Disorders: psycho-neuroimmunology and the intestinal microbiota: clinical observations and basic mechanisms,” Clinical and Experimental Immunology, vol. 160, no. 1, pp. 85–91, 2010.
[59]
S. M. Collins, M. Surette, and P. Bercik, “The interplay between the intestinal microbiota and the brain,” Nature Reviews Microbiology, vol. 10, no. 11, pp. 735–742, 2012.
[60]
I. I. Ivanov, K. Atarashi, N. Manel et al., “Induction of intestinal Th17 cells by segmented filamentous bacteria,” Cell, vol. 139, no. 3, pp. 485–498, 2009.
[61]
C. O'Mahony, P. Scully, D. O'Mahony et al., “Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-κB activation,” PLoS Pathogens, vol. 4, no. 8, Article ID e1000112, 2008.
[62]
K. Atarashi, T. Tanoue, T. Shima et al., “Induction of colonic regulatory T cells by indigenous Clostridium species,” Science, vol. 331, no. 6015, pp. 337–341, 2011.
[63]
A. Jamshidian, V. Shaygannejad, A. Pourazar, S. H. Zarkesh-Esfahani, and M. Gharagozloo, “Biased Treg/Th17 balance away from regulatory toward inflammatory phenotype in relapsed multiple sclerosis and its correlation with severity of symptoms,” Journal of Neuroimmunology, vol. 262, no. 1-2, pp. 106–112, 2013.
[64]
S. Lavasani, B. Dzhambazov, M. Nouri et al., “A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells,” PLoS ONE, vol. 5, no. 2, Article ID e9009, 2010.
[65]
J. Ochoa-Repáraz, D. W. Mielcarz, L. E. Ditrio et al., “Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 183, no. 10, pp. 6041–6050, 2009.
[66]
J. Ochoa-Repáraz, D. W. Mielcarz, Y. Wang et al., “A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease,” Mucosal Immunology, vol. 3, no. 5, pp. 487–495, 2010.
[67]
Y. K. Lee, J. S. Menezes, Y. Umesaki, and S. K. Mazmanian, “Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, supplement 1, pp. 4615–4622, 2011.
[68]
K. Berer, M. Mues, M. Koutrolos et al., “Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination,” Nature, vol. 479, no. 7374, pp. 538–541, 2011.
[69]
T. Muchamuel, M. Basler, M. A. Aujay et al., “A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis,” Nature Medicine, vol. 15, no. 7, pp. 781–787, 2009.
[70]
K. W. Kalim, M. Basler, C. J. Kirk, and M. Groettrup, “Immunoproteasome subunit LMP7 deficiency and inhibition suppresses Th1 and Th17 but enhances regulatory T cell differentiation,” Journal of Immunology, vol. 189, no. 8, pp. 4182–4193, 2012.
[71]
W. Strober, I. Fuss, and P. Mannon, “The fundamental basis of inflammatory bowel disease,” Journal of Clinical Investigation, vol. 117, no. 3, pp. 514–521, 2007.
[72]
N. Schmidt, E. Gonzalez, A. Visekruna et al., “Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis,” Gut, vol. 59, no. 7, pp. 896–906, 2010.
[73]
M. Basler, M. Dajee, C. Moll, M. Groettrup, and C. J. Kirk, “Prevention of experimental colitis by a selective inhibitor of the immunoproteasome,” Journal of Immunology, vol. 185, no. 1, pp. 634–641, 2010.
[74]
S. Oh, C. Cudrici, T. Ito, and H. Rus, “B-cells and humoral immunity in multiple sclerosis. Implications for therapy,” Immunologic Research, vol. 40, no. 3, pp. 224–234, 2008.
[75]
P. Engel, J. A. Gómez-Puerta, M. Ramos-Casals, F. Lozano, and X. Bosch, “Therapeutic targeting of B cells for rheumatic autoimmune diseases,” Pharmacological Reviews, vol. 63, no. 1, pp. 127–156, 2011.
[76]
A. C. Chan, “B cell immunotherapy in autoimmunity: 2010 update,” Molecular Immunology, vol. 48, no. 11, pp. 1344–1347, 2011.
[77]
B. Serafini, B. Rosicarelli, R. Magliozzi, E. Stigliano, and F. Aloisi, “Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis,” Brain Pathology, vol. 14, no. 2, pp. 164–174, 2004.
[78]
M. Duddy, M. Niino, F. Adatia et al., “Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis,” Journal of Immunology, vol. 178, no. 10, pp. 6092–6099, 2007.
[79]
A. Bar-Or, L. Fawaz, B. Fan et al., “Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?” Annals of Neurology, vol. 67, no. 4, pp. 452–461, 2010.
[80]
K. Hawker, P. O'Connor, M. S. Freedman et al., “Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial,” Annals of Neurology, vol. 66, no. 4, pp. 460–471, 2009.
[81]
S. L. Hauser, E. Waubant, D. L. Arnold et al., “B-cell depletion with rituximab in relapsing-remitting multiple sclerosis,” The New England Journal of Medicine, vol. 358, no. 7, pp. 676–688, 2008.
[82]
N. L. Monson, P. D. Cravens, E. M. Frohman, K. Hawker, and M. K. Racke, “Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis,” Archives of Neurology, vol. 62, no. 2, pp. 258–264, 2005.
[83]
L. Kappos, D. Li, P. A. Calabresi et al., “Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial,” The Lancet, vol. 378, no. 9805, pp. 1779–1787, 2011.
[84]
S. Lulu and E. Waubant, “Humoral-targeted immunotherapies in multiple sclerosis,” Neurotherapeutics, vol. 10, no. 1, pp. 34–43, 2013.
[85]
S. E. Hensley, D. Zanker, B. P. Dolan et al., “Unexpected role for the immunoproteasome subunit LMP2 in antiviral humoral and innate immune responses,” Journal of Immunology, vol. 184, no. 8, pp. 4115–4122, 2010.
[86]
M. Maldonado, R. J. Kapphahn, M. R. Terluk et al., “Immunoproteasome deficiency modifies the alternative pathway of NFkappaB signaling,” PLoS ONE, vol. 8, no. 2, Article ID e56187, 2013.
[87]
M. W. Lin, D. Suan, K. Lenton et al., “Differentiating patterns of oligoclonal banding in the cerebrospinal fluid improves diagnostic utility for multiple sclerosis,” Pathology, vol. 44, no. 3, pp. 248–250, 2012.
[88]
O. Stich, S. Jarius, B. Kleer, C. Rasiah, R. Voltz, and S. Rauer, “Specific antibody index in cerebrospinal fluid from patients with central and peripheral paraneoplastic neurological syndromes,” Journal of Neuroimmunology, vol. 183, no. 1-2, pp. 220–224, 2007.
[89]
M. K. Storch, S. Piddlesden, M. Haltia, M. Iivanainen, P. Morgan, and H. Lassmann, “Multiple sclerosis: in situ evidence for antibody- and complement-mediated demyelination,” Annals of Neurology, vol. 43, no. 4, pp. 465–471, 1998.
[90]
I. Mayo, J. Arribas, P. Villoslada et al., “The proteasome is a major autoantigen in multiple sclerosis,” Brain, vol. 125, no. 12, pp. 2658–2667, 2002.
[91]
H. Thuy-Tien, M. Haugen, J. Aarseth, A. Storstein, and C. A. Vedeler, “Proteasome antibodies in patients with cancer or multiple sclerosis,” Scandinavian Journal of Immunology, vol. 67, no. 4, pp. 400–403, 2008.
[92]
N. H. Beyer, J. Milthers, B. A.-M. Lauridsen, G. Houen, and L. J. Frederiksen, “Autoantibodies to the proteasome in monosymptomatic optic neuritis may predict progression to multiple sclerosis,” Scandinavian Journal of Clinical and Laboratory Investigation, vol. 67, no. 7, pp. 696–706, 2007.
[93]
M. Brychcy, U. Kuckelkorn, G. Hausdorf et al., “Anti-20S proteasome autoantibodies inhibit proteasome stimulation by proteasome activator PA28,” Arthritis and Rheumatism, vol. 54, no. 7, pp. 2175–2183, 2006.
[94]
S. U. Sixt and B. Dahlmann, “Extracellular, circulating proteasomes and ubiquitin: incidence and relevance,” Biochimica et Biophysica Acta, vol. 1782, no. 12, pp. 817–823, 2008.
[95]
C. Jakob, K. Egerer, P. Liebisch et al., “Circulating proteasome levels are an independent prognostic factor for survival in multiple myeloma,” Blood, vol. 109, no. 5, pp. 2100–2105, 2007.
[96]
O. Mueller, T. Anlasik, J. Wiedemann et al., “Circulating extracellular proteasome in the cerebrospinal fluid: a study on concentration and proteolytic activity,” Journal of Molecular Neuroscience, vol. 46, no. 3, pp. 509–515, 2012.
[97]
R. C. Lai, S. S. Tan, B. J. Teh et al., “Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome,” International Journal of Proteomics, vol. 2012, Article ID 971907, 14 pages, 2012.
[98]
G. A. Roth, B. Moser, C. Krenn et al., “Heightened levels of circulating 20S proteasome in critically ill patients,” European Journal of Clinical Investigation, vol. 35, no. 6, pp. 399–403, 2005.
[99]
A. Minagar, W. Ma, X. Zhang et al., “Plasma ubiquitin-proteasome system profile in patients with multiple sclerosis: correlation with clinical features, neuroimaging, and treatment with interferon-beta-1b,” Journal of Neurology Research, vol. 34, no. 6, pp. 611–618, 2012.
[100]
C. Stadelmann, C. Wegner, and W. Brück, “Inflammation, demyelination, and degeneration: recent insights from MS pathology,” Biochimica et Biophysica Acta, vol. 1812, no. 2, pp. 275–282, 2011.
[101]
R. E. Gonsette, “Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity,” Journal of the Neurological Sciences, vol. 274, no. 1-2, pp. 48–53, 2008.
[102]
H. Lassmann and J. van Horssen, “The molecular basis of neurodegeneration in multiple sclerosis,” FEBS Letters, vol. 585, no. 23, pp. 3715–3723, 2011.
[103]
L. Haider, M. T. Fischer, J. M. Frischer et al., “Oxidative damage in multiple sclerosis lesions,” Brain, vol. 134, no. 7, pp. 1914–1924, 2011.
[104]
S. M. Smerjac and O. A. Bizzozero, “Cytoskeletal protein carbonylation and degradation in experimental autoimmune encephalomyelitis,” Journal of Neurochemistry, vol. 105, no. 3, pp. 763–772, 2008.
[105]
J. Zheng and O. A. Bizzozero, “Accumulation of protein carbonyls within cerebellar astrocytes in murine experimental autoimmune encephalomyelitis,” Journal of Neuroscience Research, vol. 88, no. 15, pp. 3376–3385, 2010.
[106]
L. Papa and P. Rockwell, “Persistent mitochondrial dysfunction and oxidative stress hinder neuronal cell recovery from reversible proteasome inhibition,” Apoptosis, vol. 13, no. 4, pp. 588–599, 2008.
[107]
P. G. Sullivan, N. B. Dragicevic, J.-H. Deng et al., “Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover,” Journal of Biological Chemistry, vol. 279, no. 20, pp. 20699–20707, 2004.
[108]
C. T. Aiken, R. M. Kaake, X. Wang, and L. Huang, “Oxidative stress-mediated regulation of proteasome complexes,” Molecular and Cellular Proteomics, vol. 10, no. 5, Article ID R110.006924, 2011.
[109]
S. Grimm, A. H？hn, and T. Grune, “Oxidative protein damage and the proteasome,” Amino acids, vol. 42, no. 1, pp. 23–38, 2012.
[110]
T. Jung and T. Grune, “The proteasome and its role in the degradation of oxidized proteins,” IUBMB Life, vol. 60, no. 11, pp. 743–752, 2008.
[111]
T. Grune, K. Merker, G. Sandig, and K. J. A. Davies, “Selective degradation of oxidatively modified protein substrates by the proteasome,” Biochemical and Biophysical Research Communications, vol. 305, no. 3, pp. 709–718, 2003.
[112]
L. Farout and B. Friguet, “Proteasome function in aging and oxidative stress: implications in protein maintenance failure,” Antioxidants and Redox Signaling, vol. 8, no. 1-2, pp. 205–216, 2006.
[113]
T. Reinheckel, N. Sitte, O. Ullrich, U. Kuckelkorn, K. J. A. Davies, and T. Grune, “Comparative resistance of the 20 S and 26 S proteasome to oxidative stress,” Biochemical Journal, vol. 335, no. 3, pp. 637–642, 1998.
[114]
M. K？stle and T. Grune, “Proteins bearing oxidation-induced carbonyl groups are not preferentially ubiquitinated,” Biochimie, vol. 93, no. 6, pp. 1076–1079, 2011.
[115]
S. Kotamraju, S. Matalon, T. Matsunaga, T. Shang, J. M. Hickman-Davis, and B. Kalyanaraman, “Upregulation of immunoproteasomes by nitric oxide: potential antioxidative mechanism in endothelial cells,” Free Radical Biology and Medicine, vol. 40, no. 6, pp. 1034–1044, 2006.
[116]
A. M. Pickering, A. L. Koop, C. Y. Teoh, G. Ermak, T. Grune, and K. J. A. Davies, “The immunoproteasome, the 20S proteasome and the PA28αβ proteasome regulator are oxidative-stress-adaptive proteolytic complexes,” Biochemical Journal, vol. 432, no. 3, pp. 585–594, 2010.
[117]
A. M. Pickering and K. J. Davies, “Differential roles of proteasome and immunoproteasome regulators Pa28alphabeta, Pa28gamma and Pa200 in the degradation of oxidized proteins,” Archives of Biochemistry and Biophysics, vol. 523, no. 2, pp. 181–190, 2012.
[118]
Q. Ding, S. Martin, E. Dimayuga, A. J. Bruce-Keller, and J. N. Keller, “LMP2 knock-out mice have reduced proteasome activities and increased levels of oxidatively damaged proteins,” Antioxidants and Redox Signaling, vol. 8, no. 1-2, pp. 130–135, 2006.
[119]
D. Bates, “Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials,” Neurology, vol. 76, supplement 1, no. 1, pp. S14–S25, 2011.
[120]
C. F. Lucchinetti, J. Parisi, and W. Bruck, “The pathology of multiple sclerosis,” Neurologic Clinics, vol. 23, no. 1, pp. 77–105, 2005.
[121]
G. Frisullo, D. Plantone, A. Marti et al., “Type 1 immune response in progressive multiple sclerosis,” Journal of Neuroimmunology, vol. 249, no. 1-2, pp. 112–116, 2012.
[122]
E. Bellavista, F. Andreoli, M. Parenti et al., “Immunoproteasome in cancer and neuropathologies: a new therapeutic target?” Current Pharmaceutical Design, vol. 19, no. 4, pp. 702–718, 2013.
[123]
A. Perchellet, I. Stromnes, J. M. Pang, and J. Goverman, “CD8+ T cells maintain tolerance to myelin basis protein by ‘epitope theft’,” Nature Immunology, vol. 5, no. 6, pp. 606–614, 2004.
[124]
M. A. Friese, K. B. Jakobsen, L. Friis et al., “Opposing effects of HLA class I molecules in tuning autoreactive CD8 + T cells in multiple sclerosis,” Nature Medicine, vol. 14, no. 11, pp. 1227–1235, 2008.
[125]
Human Microbiome Project Consortium, “Structure, function and diversity of the healthy human microbiome,” Nature, vol. 486, no. 7402, pp. 207–214, 2012.
[126]
M. Candela, E. Biagi, S. Maccaferri, S. Turroni, and P. Brigidi, “Intestinal microbiota is a plastic factor responding to environmental changes,” Trends in Microbiology, vol. 20, no. 8, pp. 385–391, 2012.
[127]
A. Perchellet, T. Brabb, and J. M. Goverman, “Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 37, pp. 14040–14045, 2008.
