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J. Biol. Chem., Vol. 283, Issue 36, 24584-24593, September 5, 2008

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Niemann-Pick C1 Functions in Regulating Lysosomal Amine Content^*

From the Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66047

Mutations in the late endosomal/lysosomal membrane protein Niemann-Pick C1 (NPC1) are known to cause a generalized block in retrograde vesicle-mediated transport, resulting in the hyper-accumulation of multiple lysosomal cargos. An important, yet often overlooked, category of lysosomal cargo includes the vast array of small molecular weight amine-containing molecules that are substrates for ion trapping in the highly acidic organelle lumen. We show here that the introduction of amine-containing molecules in lysosomes can significantly stimulate NPC1-mediated late endosome/lysosome fusion, and subsequently the secretion of lysosomal cargo. To illustrate the physiological importance of this NPC1-mediated transport pathway, we show that NPC1-deficient cells are more susceptible to the toxic effects of a lysosomotropic polyamine metabolite 3-aminopropanal. Moreover, NPC fibroblasts are shown to have higher levels of polyamine oxidase, an enzyme involved in the formation of 3-aminopropanal. Collectively, these findings provide strong support for a novel functional role for NPC1 and may also provide clues toward understanding NPC disease progression.

Received for publication, May 14, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 CA106655. This work was also supported by the Ara Parseghian Medical Research Foundation (to J. P. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Experimental Procedures," Figs. S1–S3, and references.

¹ To whom correspondence should be addressed: Dept. of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave., Lawrence KS 66047. Tel.: 785-864-2626; Fax: 785-864-5736; E-mail: krise{at}ku.edu.

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