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J. Biol. Chem., Vol. 280, Issue 35, 31333-31339, September 2, 2005

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Reduced N-Acetylaspartate Levels in Mice Lacking Aralar, a Brain- and Muscle-type Mitochondrial Aspartate-glutamate Carrier^*

Md. Abdul Jalil, Laila Begum, Laura Contreras¶||, Beatriz Pardo¶**, Mikio Iijima, Meng Xian Li, Milagros Ramos¶, Patricia Marmol¶||, Masahisa Horiuchi, Kyoko Shimotsu, Shiro Nakagawa, Akiko Okubo, Munefumi Sameshima, Yasushi Isashiki, Araceli del Arco¶, Keiko Kobayashi, Jorgina Satrústegui¶, and Takeyori Saheki¶¶

From the Department of Molecular Metabolism and Biochemical Genetics, Laboratory for Neuroanatomy, and Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan, the ^¶Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, 28049 Madrid, Spain, and the Facultad de Ciencias del Medio Ambiente, Universidad de Castilla-La Mancha, 45071 Toledo, Spain

Aralar is a mitochondrial calcium-regulated aspartate-glutamate carrier mainly distributed in brain and skeletal muscle, involved in the transport of aspartate from mitochondria to cytosol, and in the transfer of cytosolic reducing equivalents into mitochondria as a member of the malate-aspartate NADH shuttle. In the present study, we describe the characteristics of aralar-deficient (Aralar^-/-) mice, generated by a gene-trap method, showing no aralar mRNA and protein, and no detectable malate-aspartate shuttle activity in skeletal muscle and brain mitochondria. Aralar^-/- mice were growth-retarded, exhibited generalized tremoring, and had pronounced motor coordination defects along with an impaired myelination in the central nervous system. Analysis of lipid components showed a marked decrease in the myelin lipid galactosyl cerebroside. The content of the myelin lipid precursor, N-acetylaspartate, and that of aspartate are drastically decreased in the brain of Aralar^-/- mice. The defect in N-acetylaspartate production was also observed in cell extracts from primary neuronal cultures derived from Aralar^-/- mouse embryos. These results show that aralar plays an important role in myelin formation by providing aspartate for the synthesis of N-acetylaspartate in neuronal cells.

Received for publication, May 13, 2005 , and in revised form, June 27, 2005.

^* This work was supported in part by Grants-in-Aid for Scientific Research P 02524 (to M. A. J.), 16500222 (to S. N.), and 16390100 (to K. K.) from the Japan Society for the Promotion of Science (JSPS), a grant-in-aid from The Japan Medical Association (to T. S.), Dirección General de Investigación del Ministerio de Ciencia y Tecnología Grant BMC2002-02072, Comunidad de Madrid Grant 08.5/0024/2003, and Fondo de Investigaciones Sanitarias Grant 01/0395 (to J. S.), and by an institutional grant from the Fundacion Ramón Areces to the Centro de Biologia Molecular Severo Ochoa. 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.

^|| Supported by fellowships from the Comunidad de Madrid.

^** Supported by a postdoctoral contract from the Comunidad de Madrid.

^¶¶ To whom correspondence should be addressed: Dept. of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan. Tel.: 81-99-275-5239; Fax: 81-99-264-6274; E-mail: takesah{at}m.kufm.kagoshima-u.ac.jp.

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