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J. Biol. Chem., Vol. 279, Issue 25, 26167-26175, June 18, 2004

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Accumulation of Glycosphingolipids in Niemann-Pick C Disease Disrupts Endosomal Transport^*

Danielle te Vruchte, Emyr Lloyd-Evans, Robert Jan Veldman¶, David C. A. Neville, Raymond A. Dwek, Frances M. Platt, Wim J. van Blitterswijk¶, and Dan J. Sillence||

From the Glycobiology Institute, Department of Biochemistry, South Parks Road, University of Oxford, Oxford OX1 3QU, United Kingdom and ^¶Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Glycosphingolipids are endocytosed and targeted to the Golgi apparatus but are mistargeted to lysosomes in sphingolipid storage disorders. Substrate reduction therapy utilizes imino sugars to inhibit glucosylceramide synthase and potentially abrogate the effects of storage. Niemann-Pick type C (NPC) disease is a disorder of intracellular transport where glycosphingolipids (GSLs) and cholesterol accumulate in endosomal compartments. The mechanisms of altered intracellular trafficking are not known but may involve the mistargeting and disrupted function of proteins associated with GSL membrane microdomains. Membrane microdomains were isolated by Triton X-100 and sucrose density gradient ultracentrifugation. High pressure liquid chromatography and mass spectrometric analysis of NPC1^–/– mouse brain revealed large increases in GSL. Sphingosine was also found to be a component of membrane microdomains, and in NPC liver and spleen, large increases in cholesterol and sphingosine were found. GSL and cholesterol levels were increased in mutant NPC1-null Chinese hamster ovary cells as well as U18666A and progesterone induced NPC cell culture models. However, inhibition of GSL synthesis in NPC cells with N-butyldeoxygalactonojirimycin led to marked decreases in GSL but only small decreases in cholesterol levels. Both annexin 2 and 6, membrane-associated proteins that are important in endocytic trafficking, show distorted distributions in NPC cells. Altered BODIPY lactosylceramide targeting, decreased endocytic uptake of a fluid phase marker, and mistargeting of annexin 2 (phenotypes associated with NPC) are reversed by inhibition of GSL synthesis. It is suggested that accumulating GSL is part of a mislocalized membrane microdomain and is responsible for the deficit in endocytic trafficking found in NPC disease.

Received for publication, October 22, 2003 , and in revised form, April 8, 2004.

^* 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 a grant from Action Medical Research (UK).

Supported by grants from the Ara Parseghian Medical Research Foundation.

^|| To whom correspondence should be addressed: Glycobiology Institute, Dept. of Biochemistry, South Parks Rd., University of Oxford, Oxford OX1 3QU, UK. Tel.: 44-1865-275743; Fax: 44-1865-275216; E-mail: dan{at}glycob.ox.ac.uk.

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