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J. Biol. Chem., Vol. 282, Issue 45, 32655-32664, November 9, 2007

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Accumulation of Glucosylceramide in Murine Testis, Caused by Inhibition of -Glucosidase 2

IMPLICATIONS FOR SPERMATOGENESIS^*

Charlotte M. Walden¹, Roger Sandhoff, Chia-Chen Chuang^¶, Yildiz Yildiz^||, Terry D. Butters, Raymond A. Dwek, Frances M. Platt^¶, and Aarnoud C. van der Spoel^¶2

From the Departments of Biochemistry and ^¶Pharmacology, University of Oxford, Oxford OX1 3QU, United Kingdom, the Department of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany, and the ^||Department of Internal Medicine I, University Hospital Bonn, 53105 Bonn, Germany

One of the hallmarks of male germ cell development is the formation of a specialized secretory organelle, the acrosome. This process can be pharmacologically disturbed in C57BL/6 mice, and thus infertility can be induced, by small molecular sugar-like compounds (alkylated imino sugars). Here the biochemical basis of this effect has been investigated. Our findings suggest that in vivo alkylated imino sugars primarily interact with the non-lysosomal glucosylceramidase. This enzyme cleaves glucosylceramide into glucose and ceramide, is sensitive to imino sugars in vitro, and has been characterized as -glucosidase 2 (GBA2). Imino sugars raised the level of glucosylceramide in brain, spleen, and testis, in a dose-dependent fashion. In testis, multiple species of glucosylceramide were similarly elevated, those having long acyl chains (C16–24), as well as those with very long polyunsaturated acyl chains (C28–30:5). Both of these GlcCer species were also increased in the testes from GBA2-deficient mice. When considering that the very long polyunsaturated sphingolipids are restricted to germ cells, these results indicate that in the testis GBA2 is present in both somatic and germ cells. Furthermore, in all mouse strains tested imino sugar treatment caused a rise in testicular glucosylceramide, even in a number of strains, of which the males remain fertile after drug administration. Therefore, it appears that acrosome formation can be derailed by accumulation of glucosylceramide in an extralysosomal localization, and that the sensitivity of male germ cells to glucosylceramide is genetically determined.

Received for publication, March 20, 2007 , and in revised form, September 7, 2007.

^* This work was supported by National Institutes of Health NICHD Grant 1 U01 HD45861 (to A. C. S. and F. M. P.), Schering AG (to C.-C. C.), Oxford GlycoSciences, Celltech UK, and a Glycobiology Institute endowment. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Current address: Dept. of Pathology, University of Oxford, Oxford, United Kingdom.

² To whom correspondence should be addressed: Mansfield Rd., Oxford OX1 3QT, United Kingdom. Tel.: 0-1865-271607; Fax: 0-1865-271853; E-mail: aarnoud.vanderspoel{at}pharm.ox.ac.uk.

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