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J. Biol. Chem., Vol. 279, Issue 18, 19247-19256, April 30, 2004
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From the Departments of Pharmacology and Anatomy, KEIO University School of Medicine, Life Science Research Building, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Mutation of the ALS2 gene encoding alsin is linked to the onset of autosomal recessive motor neuron diseases, including juvenile-onset amyotrophic lateral sclerosis (ALS). Alsin long form (LF) belongs to the family of the guanine nucleotide exchanging factor (GEF) for small GTPases. Expression of alsin LF, but not alsin short form, protected motor neuronal cells from toxicity induced by mutants of the Cu/Zn-superoxide dismutase (SOD1) gene, which cause autosomal dominant ALS. In contrast, expression of alsin did not suppress neurotoxicity by other neurodegenerative insults such as Alzheimer's disease-related genes. Deletion analysis of alsin LF demonstrated that the RhoGEF domain is essential for alsin-mediated neuroprotection. Furthermore, we found that alsin LF bound to SOD1 mutants, but not to wtSOD1, via the RhoGEF domain. Such functional and physical interaction between two ALS-related genes will become a promising clue to clarify the pathogenesis of ALS and other motor neuron diseases.
Received for publication, December 4, 2003 , and in revised form, February 6, 2004.
* This work was supported in part by grants from Japan Society for the Promotion of Science (to K. K. and T. N.) and Keio University Grant-in-aid for Encouragement of Young Medical Scientist (to K. K.). 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.
To whom correspondence may be addressed: Depts. of Pharmacology, KEIO University School of Medicine, Life Science Research Bldg., 6th Floor, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: 81-3-5363-3751; Fax: 81-3-5363-8428; E-mail: niikurat{at}sc.itc.keio.ac.jp.
To whom correspondence may be addressed: Dept. of Pharmacology, KEIO University School of Medicine, Life Science Research Bldg., 6th Floor, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: 81-3-5363-3751; Fax: 81-3-5363-8428; E-mail: sakimatu{at}sc.itc.keio.ac.jp.
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