title: Altered transition metal homeostasis in Niemann-Pick disease, type C1.
abstract: The loss of NPC1 protein function is the predominant cause of Niemann-Pick type C1 disease (NP-C1), a systemic and neurodegenerative disorder characterized by late-endosomal/lysosomal accumulation of cholesterol and other lipids. Limited evidence from post-mortem human tissues, an Npc1(-/-) mouse model, and cell culture studies also suggest failure of metal homeostasis in NP-C1. To investigate these findings, we performed a comprehensive transition metal analysis of cerebrospinal fluid (CSF), plasma and tissue samples from human NP-C1 patients and an Npc1(-/-) mouse model. NPC1 deficiency in the Npc1(-/-) mouse model resulted in a perturbation of transition metal homeostasis in the plasma and key organs (brain, liver, spleen, heart, lungs, and kidneys). Analysis of human patient CSF, plasma and post-mortem brain tissues also indicated disrupted metal homeostasis. There was a disparity in the direction of metal changes between the human and the Npc1(-/-) mouse samples, which may reflect species-specific metal metabolism. Nevertheless, common to both species is brain zinc accumulation. Furthermore, treatment with the glucosylceramide synthase inhibitor miglustat, the only drug shown in a controlled clinical trial to have some efficacy for NP-C1, did not correct the alterations in CSF and plasma transition metal and ceruloplasmin (CP) metabolism in NP-C1 patients. These findings highlight the importance of NPC1 function in metal homeostasis, and indicate that metal-targeting therapy may be of value as a treatment for NP-C.
authors.affiliation: Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Level 4, Kenneth Myer Building, Parkville, Victoria 3010, Australia. ashley.bush@florey.edu.au.
authors.forename: Ya Hui
authors.initials: YH
authors.lastname: Hung
authors.forename: Noel G
authors.initials: NG
authors.lastname: Faux
authors.forename: David W
authors.initials: DW
authors.lastname: Killilea
authors.forename: Nicole
authors.initials: N
authors.lastname: Yanjanin
authors.forename: Sally
authors.initials: S
authors.lastname: Firnkes
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.forename: George
authors.initials: G
authors.lastname: Ganio
authors.forename: Mark
authors.initials: M
authors.lastname: Walterfang
authors.forename: Caroline
authors.initials: C
authors.lastname: Hastings
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002570:Ceruloplasmin / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D017353:Gene Deletion; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008670:Metals / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D028561:Transition Elements / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008670:Metals; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D028561:Transition Elements; D017485:1-Deoxynojirimycin; C059896:miglustat; D002570:Ceruloplasmin