Jump to main content
Jump to site search

Issue 3, 2014
Previous Article Next Article

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

Author affiliations


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.

Graphical abstract: Altered transition metal homeostasis in Niemann–Pick disease, type C1

Back to tab navigation

Supplementary files

Article information

15 Oct 2013
26 Nov 2013
First published
26 Nov 2013

Metallomics, 2014,6, 542-553
Article type
Author version available

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

Y. H. Hung, N. G. Faux, D. W. Killilea, N. Yanjanin, S. Firnkes, I. Volitakis, G. Ganio, M. Walterfang, C. Hastings, F. D. Porter, D. S. Ory and A. I. Bush, Metallomics, 2014, 6, 542
DOI: 10.1039/C3MT00308F

Social activity

Search articles by author