[Frontiers in Bioscience, Landmark, 20, 303-313, January 1, 2015]

Lipid rafts and their possible involvements in neuroimmunological disorders: new research arena

Kunihiko Asakura 1 , Akihiro Ueda 1 , Tatsuro Mutoh 1

1Department of Neurology, Fujita Health University, Toyoake, Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Multiple sclerosis
    3.1. Exploration of key molecules regarding the pathogenesis of MS
    3.2.αB-crystallin
    3.3. Statins
    3.4. Fingolimod
    3.5. Remyelination promoting antibody
4. Neuromyelitis optica
    4.1. Aquaporin-4
    4.2. Other aquaporins
5. Conclusion
6. References

1. ABSTRACT

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are presumed to be an autoimmune disease in the central nervous system (CNS). Although lipids are most abundant components in the nervous system, it has been believed that cellular and/or humoral immunity to various myelin proteins causes these neuroinflammatory diseases. Recent research advances enable us to study lipids in the membranes and some key molecules involved in various neurological disorders including Guillain–Barré syndrome, Alzheimer’s disease, Parkinson’s disease, and prion disease, are localized in lipid rafts. In MS and NMO, the key molecules for the pathogenesis or the target molecules for the treatments of MS and NMO are also localized in lipid rafts. Here in this article, we highlight on the possible involvement of lipid rafts in the pathogenesis and treatment of MS and NMO and introduce our recent observation of aquaporin 4 regarding NMO.

6. REFERENCES

1. A Ueda, S Shima, T Miyashita, S Ito, M Ueda, S Kusunoki, K Asakura & T Mutoh: Anti-GM1 antibodies affect the integrity of lipid rafts. Mol Cell Neurosci 45, 355-362 (2010)
DOI: 10.1016/j.mcn.2010.07.008

2. R Ehehalt, P Keller, C Haass, C Thiele & K Simons. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol 160, 113-123 (2003)
DOI: 10.1083/jcb.200207113

3. DL Fortin, MD Troyer, K Nakamura, S Kubo, MD Anthony & RH Edwards: Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci 24, 6715-6723 (2004)
DOI: 10.1523/JNEUROSCI.1594-04.2004

4. NM Hooper: Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein. Biochem Soc Trans 33, 335-338 (2005)
DOI: 10.1042/BST0330335

5. T Mutoh, T A Tokuda, T Miyadai, M Hamaguchi & N Fujiki: Ganglioside GM1 binds to the Trk protein and regulates receptor function. Proc Nat Acad Sci, USA 92, 5087-5091 (1995)
DOI: 10.1073/pnas.92.11.5087

6. T Mutoh, A Tokuda, J Inokuchi & M Kuriyama: Glucosylceramide synthase inhibitor inhibits the action of nerve growth factor in PC12 cells. J Biol Chem 273, 26001-26007 (1998)
DOI: 10.1074/jbc.273.40.26001

7. PV Lehmann, T Forsthuber, A Miller & EE Sercarz: Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 358, 155-157 (1992)
DOI: 10.1038/358155a0

8. CP Genain, B Cannella, SL Hauser & CS Raine: Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nature Med 5, 170-175 (1999)
DOI: 10.1038/5532

9. MC Levin, S Lee, LA Gardner, Y Shin, JN Douglas & C Cooper: Autoantibodies to Non-myelin Antigens as Contributors to the Pathogenesis of Multiple Sclerosis. J Clin Cell Immunol 4,
DOI: 10.4172/2155-9899.1000148 (2013)

10. JL Kanter, Narayana, PP Ho, Catz, KG Warren, RA Sobel, L Steinman & WH Robinson: Lipid microarrays identify key mediators of S immune brain inflammation. Nature Med 12, 138-143 (2006)
DOI: 10.1038/nm1344

11. JM van Noort, AC van Sechel, JJ Bajramovic, M el Ouagmiri, CH Polman, H Lassmann & R Ravid: The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis. Nature 375, 798-801 (1995)
DOI: 10.1038/375798a0

12. RK Gangalum, IC Atanasov, ZH Zhou & SP Bhat: AlphaB-crystallin is found in detergent-resistant membrane microdomains and is secreted via exosomes from human retinal pigment epithelial cells. J Biol Chem 286, 3261-3269 (2011)
DOI: 10.1074/jbc.M110.160135

13. JC LaRosa, J He & S Vupputuri: Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 282, 2340-2346 (1999)
DOI: 10.1001/jama.282.24.2340

14. R Kolesnick: The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J Clin Invest 110, 3-8 (2002)
DOI: 10.1172/JCI0216127

15. EC Jury, DA Isenberg, C Mauri & MR Ehrenstein: Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. J Immunol 177, 7416-7422 (2006)
DOI: 10.4049/jimmunol.177.10.7416

16. S Markovic-Plese, AK Singh & I Singh: Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair. Future Neurol 3,153 (2008)
DOI: 10.2217/14796708.3.2.153

17. JK Liao: Isoprenoids as mediators of the biological effects of statins. J Clin Invest 110, 285-288 (2002)
DOI: 10.1172/JCI0216421

18. J Wang, Y Xiao, M Luo & H Luo: Statins for multiple sclerosis. The Cochrane database of systematic reviews: CD008386. (2011)
DOI: 10.1002/14651858

19. L Kappos, EW Radue, P O’Connor, C Polman, R Hohlfeld, P Calabresi, K Selmaj, C Agoropoulou, M Leyk, L Zhang-Auberson, P Burtin & Freedoms Study Group FS: A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New Engl J Med 362, 387-401 (2010)
DOI: 10.1056/NEJMoa0909494

20. JA Cohen, F Barkhof, G Comi, HP Hartung, BO Khatri, X Montalban, J Pelletier, R Capra, P Gallo, G Izquierdo, K Tiel-Wilck, A de Vera, J J in, T Stites, S Wu, S Aradhye, L Kappos & Transforms Study Group: Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. New Engl J Med 362, 402-415 (2010)
DOI: 10.1056/NEJMoa0907839

21. V Brinkmann: FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharma 158, 1173-1182 (2009)
DOI: 10.1111/j.1476-5381.2009.00451.x

22. E Sawicka, G Dubois, G Jarai, M Edwards, M Thomas, A Nicholls, R Albert, C Newson, V Brinkmann & C Walker: The sphingosine 1-phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/CD25+ T-regulatory cells and enhances their functional activity. J Immunol 175, 7973-7980 (2005)
DOI: 10.4049/jimmunol.175.12.7973

23. C Daniel, N Sartory, N Zahn, G Geisslinger, HH Radeke & JM Stein. FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells. J Immunol 178, 2458-2468 (2007)
DOI: 10.4049/jimmunol.178.4.2458

24. S Sehrawat, BT Rouse: Anti-inflammatory effects of FTY720 against viral-induced immunopathology: role of drug-induced conversion of T cells to become Foxp3+ regulators. J Immunol 180, 7636-7647 (2008)
DOI: 10.4049/jimmunol.180.11.7636

25. R van Doorn, J van Horssen, D Verzijl, M Witte, E Ronken, B van Het Hof, K Lakeman, CD Dijkstra, P van Der Valk, A Reijerkerk, AE Alewijnse, SL Peters & HE De Vries: Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia 58, 1465-1476 (2010)
DOI: 10.1002/glia.21021

26. M Rodriguez, VA Lennon, EN Benveniste & JE Merrill: Remyelination by oligodendrocytes stimulated by antiserum to spinal cord. J Neuropathol Exp Neurol 46, 84-95 (1987)
DOI: 10.1097/00005072-198701000-00008

27. M Rodriguez, VA Lennon: Immunoglobulins promote remyelination in the central nervous system. Ann Neurol 27, 12-17 (1990)
DOI: 10.1002/ana.410270104

28. DJ Miller, KS Sanborn, JA Katzmann & M Rodriguez: Monoclonal autoantibodies promote central nervous system repair in an animal model of multiple sclerosis. J Neurosci 14, 6230-6238 (1994)

29. K Asakura, DJ Miller, LR Pease & M Rodriguez: Targeting of IgMκ antibodies to oligodendrocytes promotes CNS remyelination. J Neurosci 18, 7700-7708 (1998)

30. DJ Miller, M Rodriguez: A monoclonal autoantibody that promotes central nervous system remyelination in a model of multiple sclerosis is a natural autoantibody encoded by germline immunoglobulin genes. J Immunol 154, 2460-2469 (1995)

31. K Asakura, DJ Miller, RJ Pogulis, LR Pease & M Rodriguez: Oligodendrocyte-reactive O1, O4, and HNK-1 monoclonal antibodies are encoded by germline immunoglobulin genes. Mol Brain Res 34, 283-293 (1995)
DOI: 10.1016/0169-328X(95)00190-4

32. K Asakura, DJ Miller, K Murray, R Bansal, SE Pfeiffer & M Rodriguez: Monoclonal autoantibody SCH94.0.3, which promotes central nervous system remyelination, recognizes an antigen on the surface of oligodendrocytes. J Neurosci Res 43, 273-281 (1996)
DOI: 10.1002/(SICI)1097-4547(19960201)43:3<273::AID-JNR2>3.0.CO;2-G

33. DJ Miller, JJ Bright, S Sriram & M Rodriguez: Successful treatment of established relapsing experimental autoimmune encephalomyelitis in mice with a monoclonal natural autoantibody. J Neuroimmunol 75, 204-209 (1997)
DOI: 10.1016/S0165-5728(97)00027-1

34. KD Pavelko, BG van Engelen & M Rodriguez: Acceleration in the rate of CNS remyelination in lysolecithin-induced demyelination. J Neurosci 18, 2498-2505 (1998)

35. AE Warrington, K Asakura, AJ Bieber, B Ciric, V Van Keulen, SV Kaveri, RA Kyle, LR Pease & M Rodriguez: Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Nat Acad Sci, USA 97, 6820-6825 (2000)
DOI: 10.1073/pnas.97.12.6820

36. Y Mitsunaga, B Ciric, V Van Keulen, AE Warrington, M Paz Soldan, AJ Bieber, M Rodriguez & LR Pease: Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease. FASEB J 16, 1325-1327 (2002)

37. CL Howe, AJ Bieber, AE Warrington, P LR ease & M Rodriguez: Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody. Neurobiol Dis 15, 120-131 (2004)
DOI: 10.1016/j.nbd.2003.09.002

38. J Watzlawik, E Holicky, DD Edberg, DL Marks, AE Warrington, BR Wright, RE Pagano & M Rodriguez: Human remyelination promoting antibody inhibits apoptotic signaling and differentiation through Lyn kinase in primary rat oligodendrocytes. Glia 58, 1782-1793 (2010)
DOI: 10.1002/glia.21048

39. X Xu, AE Warrington, BR Wright, AJ Bieber, V Van Keulen, LR Pease & M Rodriguez: A human IgM signals axon outgrowth: coupling lipid raft to microtubules. J Neurochem 119, 100-112 (2011)
DOI: 10.1111/j.1471-4159.2011.07416.x

40. E Devic: Myelite subaigue compliquee de nevrite optique. Bull Med (Paris) 8, 1033-1034 (1894)

41. DM Wingerchuk, WF Hogancamp, PC O’Brien & BG Weinshenker: The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 53, 1107-1114 (1999)
DOI: 10.1212/WNL.53.5.1107

42. VA Lennon, DM Wingerchuk, TJ Kryzer, SJ Pittock, CF Lucchinetti, K Fujihara, I Nakashima & BG Weinshenker: A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364, 2106-2112 (2004)
DOI: 10.1016/S0140-6736(04)17551-X

43. VA Lennon, TJ Kryzer, SJ Pittock, AS Verkman & SR Hinson: IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202, 473-477 (2005)
DOI: 10.1084/jem.20050304

44. DM Wingerchuk, VA Lennon, SJ Pittock, CF Lucchinetti & BG Weinshenker: Revised diagnostic criteria for neuromyelitis optica. Neurology 66, 1485-1489 (2006)
DOI: 10.1212/01.wnl.0000216139.44259.74

45. T Takahashi, K Fujihara, I Nakashima, T Misu, I Miyazawa, M Nakamura, S Watanabe, Y Shiga, C Kanaoka, J Fujimori, S Sato & Y Itoyama: Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 130, 1235-1243 (2007)
DOI: 10.1093/brain/awm062

46. T Matsuoka, T Matsushita, Y Kawano, M Osoegawa, H Ochi, T Ishizu, M Minohara, H Kikuchi, F Mihara, Y Ohyagi & J Kira: Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese. Brain 130, 1206-1223 (2007)
DOI: 10.1093/brain/awm027

47. DM Wingerchuk, VA Lennon, CF Lucchinetti, SJ Pittock & BG Weinshenker: The spectrum of neuromyelitis optica. Lancet Neurol 6, 805-815 (2007)
DOI: 10.1016/S1474-4422(07)70216-8

48. JL Bennett, C Lam, SR Kalluri, P Saikali, K Bautista, C Dupree, M Glogowska, D Case, JP Antel, GP Owens, D Gilden, S Nessler, C Stadelmann & B Hemmer: Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol 66, 617-629 (2009)
DOI: 10.1002/ana.21802

49. M Bradl, T Misu, T Takahashi, M Watanabe, S Mader, M Reindl, M Adzemovic, J Bauer, T Berger, K Fujihara, Y Itoyama & H Lassmann: Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann Neurol 66, 630-643 (2009)
DOI: 10.1002/ana.21837

50. S Nielsen, N EA agelhus, M Amiry-Moghaddam, C Bourque, P Agre & OP Ottersen: Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17, 171-180 (1997)

51. T Misu, K Fujihara, A Kakita, H Konno, M Nakamura, S Watanabe, T Takahashi, I Nakashima, T H akahashi & Y Itoyama: Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain 130, 1224-1234 (2007)
DOI: 10.1093/brain/awm047

52. H Suzuki, K Nishikawa, Y Hiroaki & Y Fujiyoshi: Formation of aquaporin-4 arrays is inhibited by palmitoylation of N-terminal cysteine residues. Biochim Biophys Acta 1778, 1181-1189 (2008)
DOI: 10.1016/j.bbamem.2007.12.007

53. I Levental, D Lingwood, M Grzybek, U Coskun & K Simons: Palmitoylation regulates raft affinity for the majority of integral raft proteins. Proc Nat Acad Sci, USA 107, 22050-22054 (2010)
DOI: 10.1073/pnas.1016184107

54. G Noël, DK Tham & H Moukhles: Interdependence of laminin-mediated clustering of lipid rafts and the dystrophin complex in astrocytes. J Biol Chem 284, 19694-19704 (2009)
DOI: 10.1074/jbc.M109.010090

55. GM Preston, TP Carroll, WB Guggino & P Agre: Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science 256, 385-387 (1992)
DOI: 10.1126/science.256.5055.385

56. AS Verkman. More than just water channels: unexpected cellular roles of aquaporins. J Cell Sci 118, 3225-3232 (2005)
DOI: 10.1242/jcs.02519

57. JM Crane, AS Verkman. Long-range nonanomalous diffusion of quantum dot-labeled aquaporin-1 water channels in the cell plasma membrane. Biophysical J 94, 702-713 (2008)
DOI: 10.1529/biophysj.107.115121

58. Y Ishikawa, Z Yuan, N Inoue, MT Skowronski, Y Nakae, M Shono, G Cho, M Yasui, P Agre & S Nielsen: Identification of AQP5 in lipid rafts and its translocation to apical membranes by activation of M3 mAChRs in interlobular ducts of rat parotid gland. Am J Physiol Cell Physiol 289, C1303-1311 (2005)
DOI: 10.1152/ajpcell.00211.2005

59. RJ Cenedella, PS Sexton, L Brako, WK Lo & RF Jacob: Status of caveolin-1 in various membrane domains of the bovine lens. Exp Eye Res 85, 473-481 (2007)
DOI: 10.1016/j.exer.2007.05.011

60. KM Lindsey Rose, RG Gourdie, AR Prescott, RA Quinlan, RK Crouch & KL Schey. The C terminus of lens aquaporin 0 interacts with the cytoskeletal proteins filensin and CP49. Invest Ophthalmol Vis Sci 47, 1562-1570 (2006)
DOI: 10.1167/iovs.05-1313

61. A Mazzone, P Tietz, J J efferson, R Pagano & LaRusso NF: Isolation and characterization of lipid microdomains from apical and basolateral plasma membranes of rat hepatocytes. Hepatology 43, 287-296 (2006)
DOI: 10.1002/hep.21039

Key Words: Lipid Rafts, Multiple Sclerosis, Neuromyelitis Optica, Review

Send correspondence to: Kunihiko Asakura, Department of Neurology, Fujita Health University School of Medicine, 1-98 Kutsukake-cho, Toyoake, Aichi Pref., 470-1192, Japan, Tel: 81-562-93-9295, Fax: 81-562-93-1856, E-mail: kasakura@fujita-hu.ac.jp