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J. Biol. Chem., Vol. 282, Issue 27, 19692-19699, July 6, 2007

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ABCA2 Deficiency Results in Abnormal Sphingolipid Metabolism in Mouse Brain^*

Hiromichi Sakai, Yukiko Tanaka, Makoto Tanaka, Nobuhiro Ban^¶, Katsuya Yamada^¶1, Yoshihiro Matsumura, Daisuke Watanabe^||, Mayumi Sasaki^**, Toru Kita, and Nobuya Inagaki^¶2**

From the Department of Physiology, Akita University School of Medicine, Akita 010-8543, Departments of Geriatric Medicine, Cardiovascular Medicine, ^**Diabetes and Clinical Nutrition, and ^¶Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, and ^||AT Laboratory Co., Ltd., Akita 010-0061, Japan

ABCA2, a member of the ATP-binding cassette (ABC) transporter family, is localized mainly to late endosome/lysosomes of oligodendrocytes in brain, but the physiological role and function of ABCA2 are unknown. In this study, we generated mutant mice (ABCA2-null) by targeting the abca2 gene. ABCA2-null mice exhibited a phenotype including lower pregnancy rate and body weight, shorter latency period on the balance beam, and sensitization to environmental stress compared with wild type mice but no abnormality in the cytoarchitectonic and compact myelin structure or oligodendroglial differentiation. Lipid analysis of brain from 11 days to 64 weeks of age revealed significant accumulation of gangliosides along with reduced sphingomyelin (SM) from 4 weeks to 64 weeks of age and accumulation of cerebrosides and sulfatides at 64 weeks of age in ABCA2-null mice compared with wild type mice. In addition, a significant accumulation of the major ganglioside GM1 and reduced SM was detected in the myelin fraction of ABCA2-null brain. Comparison of ABCA2-null and wild type mice revealed weak ABCA2 immunoreactivity in some large pyramidal cells of wild type brain. These results suggest that ABCA2 is involved in the intracellular metabolism of sphingolipids in the brain, particularly SM and gangliosides in oligodendrocytes and certain neurons.

Received for publication, December 1, 2006 , and in revised form, April 17, 2007.

^* This work was supported by Scientific Research Grants and the Grant-in-aid for Creative Scientific Research (15GS0301) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Physiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.

² To whom correspondence should be addressed: Dept. of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: 81-75-751-3562; Fax: 81-75-771-6601; E-mail: inagaki{at}metab.kuhp.kyoto-u.ac.jp.

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