Review Metazoan and microbial models of Niemann–Pick Type C disease Katsumi Higaki a,1,2 , Dorca Almanzar-Paramio b,2 , Stephen L. Sturley a,c, * a The Institute of Human Nutrition, Columbia University College of Physicians and Surgeons, 630 W168th St. New York, NY 10032, USA b Department of Pharmacology, Columbia University College of Physicians and Surgeons, 630 W168th St. New York, NY 10032, USA c Department of Pediatrics, Columbia University College of Physicians and Surgeons, 630 W168th St. New York, NY 10032, USA Available online 1 September 2004 Abstract Niemann–Pick Type C (NP-C) disease compellingly provides insight into lipid transport and the association of this process with severe neuronal dysfunction. The two genes that define this syndrome, NPC1 and NPC2, are conserved throughout much of eukaryotic evolution, to the extent that the yeast and mammalian NPC1 genes are functionally interchangeable. We present here an evolutionary perspective of the genes defective in NP-C disease. We will describe how conservation of sequences and their biological roles in a variety of microbial and metazoan model systems may act as roadmaps to understanding this syndrome in humans. D 2004 Published by Elsevier B.V. Keywords: Cholesterol; Sphingolipid; Niemann–Pick type C; Yeast; NPC1; NPC2; NCR1 1. Introduction The movement of sterols between and within organelles is a phenomenon common to all eukaryotic cells, from yeast to humans. In addition to being ubiquitously critical to the integrity of plasma membranes, mammalian sterols must be translocated to sites distinct from their points of synthesis (predominantly the endoplasmic reticulum) or uptake (the plasma membrane) for conversion to steryl esters, steroid hormones or bile acids. Cells must also deal with the challenge of utilizing or detoxifying sterols encountered in the external environment. When these events are defective or unregulated in humans, disease states can ensue. Much of the molecular basis of sterol homeostasis has become apparent by the isolation of several genes for monogenic human disorders (reviewed in Ref. [1]). Niemann–Pick type C (NP-C) disease is a recessive neurodegenerative lysosomal storage disorder, the established biochemical hallmark of which is the accumulation of low density lipoprotein (LDL) derived (i.e., environmental) cholesterol [2]. The genes defective in NP-C disease, NPC1 [3,4] and NPC2 [5], have recently been described, and yet the mechanisms that move sterol and other lipids around the cell are still obscure. It is important to note that NP-C is not exclusively a cholesterol transport disorder. Multiple lipids accumulate in the endosomal/lysosomal system of diseased cells. Indeed, in brain tissue the major accumulation is of gangliosides [6–8]. Thus, although cholesterol accumula- tion is a clear consequence of this disorder, it may not be the primary defect. The study of NP-C disease has benefited immensely from the availability of numerous naturally occurring and investigator generated reagents and models. The NPC1 gene, in which mutations account for the major cause of this disorder, is strongly conserved from yeast to humans [4], perhaps even with a bacterial ancestor [9,10]. Given this, we propose that an evolutionary perspective of the NP-C syndrome is highly informative with regard to understanding the defects that ultimately lead to manifes- tation of this disease. In this review, we will present several non-mammalian models for NP-C disease, and highlight their actual and potential contributions to 1388-1981/$ - see front matter D 2004 Published by Elsevier B.V. doi:10.1016/j.bbalip.2004.08.010 * Corresponding author. Institute of Human Nutrition, Columbia University College of Physicians and Surgeons, 650 W168th St., New York, NY 10032, USA. Tel.: +1 212 305 6304; fax: +1 212 305 3079. E-mail address: sls37@columbia.edu (S.L. Sturley). 1 Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Japan. 2 K. H. and D. A. -P. contributed equally to this article. Biochimica et Biophysica Acta 1685 (2004) 38 – 47 www.bba-direct.com