期刊
BRAIN RESEARCH
卷 1583, 期 -, 页码 237-244出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2014.08.014
关键词
Aquaporin 4; Lipid raft; Neuromyelitis optica; Methyl-beta-cyclodextrin; Simvastatin
资金
- MEXT-Supported Program for the Strategic Research Foundation at Private Universities [S1001034]
- Ministry of Education, Culture, Sports, Science and Technology [24591279, 22590945]
- Ministry of Health, Labour, and Welfare of Japan [H23-Nanchi-Ippan-017]
- Grants-in-Aid for Scientific Research [25461295, 24591279, 24790899, 26461299, 22590945] Funding Source: KAKEN
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system and is considered to be caused by the binding of NMO-IgG to aquaporin 4 (AQP4) on astrocytes, which initiates complement-dependent cytotoxicity. AQP4 has two isoforms, i.e., M1 and M23. AQP4 is considered to form heterotetramers containing both isoforms in vivo. Most of the previous studies were performed using either one of the isoforms expressing cell lines. In this study, we generated a fluorescent epitope-tagged AQP4 M1 and M23 co-expressing astrocyte cell line and examined the subcellular targeting of AQP4. In this cell line, AQP4 was targeted mostly to membrane lipid rafts fraction evidenced by sucrose density gradient ultracentrifugation followed by Western blotting with anti-AQP4 antibody. Cholesterol depletion with methyl-beta-cyclodextrin or simvastatin resulted in the dislocation (relocation) of AQP4 from lipid rafts to non-rafts fraction of the membrane and AQP4 was not internalized intracellularly. This change in the localization of AQP4 on membrane significantly reduced complement-dependent cytotoxic effects of NMO-IgG obtained from patients with NMO without affecting AQP4 orthogonal arrays. Thus, these data strongly suggest that the targeting of AQP4 in the lipid rafts is closely related to the pathogenic effects of NMO-IgG. (C) 2014 Elsevier B.V. All rights reserved.
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