title: Niemann-Pick C1 functions in regulating lysosomal amine content.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66047, USA.
authors.forename: Allyn M
authors.initials: AM
authors.lastname: Kaufmann
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krise
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D001679:Biogenic Amines / Q000378:metabolism*; D001692:Biological Transport / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D011992:Endosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008561:Membrane Fusion / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics / Q000378:metabolism; D011437:Propylamines / Q000378:metabolism*; D000097667:Polyamine Oxidase
chemical_list: D000447:Aldehydes; D001679:Biogenic Amines; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D000077296:Niemann-Pick C1 Protein; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011437:Propylamines; D000097667:Polyamine Oxidase; C106881:NPC1 protein, human; C050862:3-aminopropionaldehyde