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.
Subject(s)
Disease Models, Animal , Niemann-Pick Diseases/genetics , Niemann-Pick Diseases/metabolism , Amino Acid Sequence , Animals , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Carrier Proteins/chemistry , Carrier Proteins/genetics , Carrier Proteins/metabolism , Conserved Sequence , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Eukaryotic Cells , Evolution, Molecular , Fungal Proteins/genetics , Fungal Proteins/metabolism , Glycoproteins/chemistry , Glycoproteins/genetics , Glycoproteins/metabolism , Humans , Intracellular Signaling Peptides and Proteins , Membrane Glycoproteins/chemistry , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Molecular Sequence Data , Niemann-Pick C1 Protein , Niemann-Pick Diseases/pathology , Protein Structure, Tertiary , Sequence Homology, Amino Acid , Vesicular Transport ProteinsABSTRACT
Lipid movement between organelles is a critical component of eukaryotic membrane homeostasis. Niemann Pick type C (NP-C) disease is a fatal neurodegenerative disorder typified by lysosomal accumulation of cholesterol and sphingolipids. Expression of yeast NP-C-related gene 1 (NCR1), the orthologue of the human NP-C gene 1 (NPC1) defective in the disease, in Chinese hamster ovary NPC1 mutant cells suppressed lipid accumulation. Deletion of NCR1, encoding a transmembrane glycoprotein predominantly residing in the vacuole of normal yeast, gave no phenotype. However, a dominant mutation in the putative sterol-sensing domain of Ncr1p conferred temperature and polyene antibiotic sensitivity without changes in sterol metabolism. Instead, the mutant cells were resistant to inhibitors of sphingolipid biosynthesis and super sensitive to sphingosine and C2-ceramide. Moreover, plasma membrane sphingolipids accumulated and redistributed to the vacuole and other subcellular membranes of the mutant cells. We propose that the primordial function of these proteins is to recycle sphingolipids and that defects in this process in higher eukaryotes secondarily result in cholesterol accumulation.