Altered transition metal homeostasis in Niemann-Pick disease, type C1

Ya Hui Hung, Noel G. Faux, David W. Killilea, Nicole Yanjanin, Sally Firnkes, Irene Volitakis, George Ganio, Mark Walterfang, Caroline Hastings, Forbes D. Porter, Daniel S. Ory, Ashley I. Bush

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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.

Original languageEnglish
Pages (from-to)542-553
Number of pages12
Issue number3
StatePublished - Mar 2014


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