Article

Increased copper levels in in vitro and in vivo models of Niemann-Pick C disease.

Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Biology of Metals (Impact Factor: 3.17). 04/2012; 25(4):777-86. DOI: 10.1007/s10534-012-9546-6
Source: PubMed

ABSTRACT Niemann-Pick type C disease (NPC) is a hereditary neurovisceral atypical lipid storage disorder produced by mutations in the NPC1 and NPC2 genes. The disease is characterized by unesterified cholesterol accumulation in late endosomal/lysosomal compartments and oxidative stress. The most affected tissues are the cerebellum and the liver. The lysotropic drug U18666A (U18) has been widely used as a pharmacological model to induce the NPC phenotype in several cell culture lines. It has already been reported that there is an increase in copper content in hepatoma Hu7 cells treated with U18. We confirmed this result with another human hepatoma cell line, HepG2, treated with U18 and supplemented with copper in the media. However, in mouse hippocampal primary cultures treated under similar conditions, we did not find alterations in copper content. We previously reported increased copper content in the liver of Npc1 (-/-) mice compared to control animals. Here, we extended the analysis to the copper content in the cerebella, the plasma and the bile of NPC1 deficient mice. We did not observe a significant change in copper content in the cerebella, whereas we found increased copper content in the plasma and decreased copper levels in the bile of Npc1(-/-) mice. Finally, we also evaluated the plasma content of ceruloplasmin, and we found an increase in this primary copper-binding protein in Npc1 (-/-) mice. These results indicate cell-type dependence of copper accumulation in NPC disease and suggest that copper transport imbalance may be relevant to the liver pathology observed in NPC disease.

0 Bookmarks
 · 
137 Views
  • [Show abstract] [Hide abstract]
    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.
    Metallomics 12/2013; · 4.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Many neurodegenerative and neuropsychiatric disorders have been reported to coincide with the dysregulation of metal ions in the body and central nervous system. However, in most cases, it is not the imbalance of a single divalent metal ion but a plethora of metal ions reported to be altered. Given that different divalent metal ions are often able to bind to a protein in a competitive manner, although with different affinities, and that they might use similar transporters for uptake and regulation, it is likely that the imbalance of one metal ion will downstream affect the homeostasis of other metal ions. Thus, based on this assumption, we hypothesize that the dysregulation of a specific metal ion will lead to a characteristic biometal profile. Similar profiles might therefore be detected in various neurological disorders. Moreover, if such shared biometal profiles exist across different neurological disorders, it is possible that shared behavioural impairments in these disorders result from the imbalance in metal ion homeostasis. Thus, here, we evaluate the reported excess or deficiency of metal ions in various neurological disorders and aim to integrate reported alterations in metal ions to generate a characteristic biometal profile for the disorder. Based on this, we try to predict which alterations in biometals will be caused by the overload or deficiency of one particular metal ion. Moreover, investigating the behavioural phenotypes of rodent models suffering from alterations in biometals, we assess whether a shared behavioural phenotype exists for disorders with similar biometal profiles. Our results show that observed behavioural aspects of some neurological disorders are reflected in their specific biometal profile and mirrored by mouse models suffering from similar biometal deregulations.
    Metallomics 03/2014; · 4.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mounting evidence suggests a pivotal role of metal imbalances in protein misfolding and amyloid diseases. As such, metal ions represent a promising therapeutic target. In this context, the synthesis of chelators that also contain complementary functionalities to combat the multifactorial nature of neurodegenerative diseases is a highly topical issue. We report two new 8-hydroxyquinoline-appended cyclodextrins and highlight their multifunctional properties, including their CuII and ZnII binding abilities, and capacity to act as antioxidants and metal-induced antiaggregants. In particular, the latter property has been applied in the development of an effective assay that exploits the formation of amyloid fibrils when β-lactoglobulin A is heated in the presence of metal ions.
    Chemistry 05/2014; · 5.93 Impact Factor

Mary Carmen Vázquez