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: 2.5). 04/2012; 25(4):777-86. DOI: 10.1007/s10534-012-9546-6
Source: PubMed


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.

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    • "Brain, which contains large amounts of polysaturated fatty acids and possesses low antioxidant capacity, is particularly vulnerable [75]. Copper levels were found elevated in several brain areas in a degenerative disease as Niemann-Pick C [76], which was specifically indicated to be associated to Bipolar Disorders [77]. "
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    ABSTRACT: Wilson's disease is an inherited disorder caused by a gene located on chromosome 13, which involved copper transportation across cell membranes. The disease can cause a reduced incorporation of copper into ceruloplasmin resulting in accumulation of this metal in the liver, central nervous system, kidneys and other organs. The objective is to define the frequencies of psychiatric disorders in WD, the amount of impairment of Quality of Life [QoL] in patients with WD and the relevance of the psychiatric disorders in the QoL of people suffering by WD. This is a systematic review. The search of the significant articles was carried out in PubMed using specific key words. Such other neurological diseases, WD is characterized by chronic course and need of treatments, impairment of functional outcomes and high frequency of psychiatric symptoms, although a specific association between Bipolar Disorders and WD was recently found. Despite this, since today few studies are carried on WD patients' quality of life related to psychiatric symptoms. Some new reports showed a link between presence of Bipolar Disorders diagnosis, cerebral damage and low Qol. Prospective studies on large cohorts are required to establish the effective impact of psychiatric disorders comorbidity, particularly Bipolar Disorders, on quality of life in WD and to clarify the causal link between brain damage, psychiatric disorders and worsening of QoL.
    Clinical Practice and Epidemiology in Mental Health 09/2012; 8:102-9. DOI:10.2174/1745017901208010102
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    • "In humans accumulation of copper was associated with oxidative stress in allergic asthma patients, and introduction of nutritional supplement therapy accompanies improved oxidative stress, immune response, pulmonary function, and decrease in copper plasma levels [51]. On the other hands copper levels were elevated in several brain areas in a degenerative disease such as Niemann-Pick C [52]. Interestingly, Nieman-Pick C disease was specifically indicated to be associated with Bipolar Disorders [53]. "
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    ABSTRACT: The aim of this study was to determine the risk for Bipolar Disorder (BD) in Wilson's disease (WD) and to measure the impaired Quality of Life (QL) in BD with WD using standardized psychiatric diagnostic tools and a case control design. This was a case control study. The cases were 23 consecutive patients with WD treated at the University Hospital in Cagliari, Italy, and the controls were 92 sex- and age-matched subjects with no diagnosis of WD who were randomly selected from a database used previously for an epidemiological study. Psychiatric diagnoses according to DSM-IV criteria were determined by physicians using structured interview tools (ANTAS-SCID). QL was measured by means of SF-12. Compared to controls, WD patients had lower scores on the SF-12 and higher lifetime prevalence of DSM-IV major depressive disorders (OR = 5.7, 95% CI 2.4-17.3) and bipolar disorders (OR = 12.9, 95% CI 3.6-46.3). BD was associated with lower SF-12 in WD patients. This study was the first to show an association between BD and WD using standardized diagnostic tools and a case control design. Reports in the literature about increased schizophrenia-like psychosis in WD and a lack of association with bipolar disorders may thus have been based on a more inclusive diagnosis of schizophrenia in the past. Our findings may explain the frequent reports of loss of emotional control, hyperactivity, loss of sexual inhibition, and irritability in WD patients. This study was limited by a small sample size.
    BMC Psychiatry 05/2012; 12(1):52. DOI:10.1186/1471-244X-12-52 · 2.21 Impact Factor
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    ABSTRACT: Copper ions are well suited to facilitate formation of reactive oxygen species (ROS) that can damage biomolecules, including DNA and chromatin. That this can occur in vitro with isolated DNA or chromatin,or by exposure of cultured mammalian cells to copper complexed with various agents, has been well demonstrated. Whether that is likely to occur in vivo is not as clear. This review addresses the question of whether and how copper ions or complexes – in forms that could be present in vivo, damage DNA and chromosome structure and/or promote epigenetic changes that can lead to pathology and diseases, including cancer and neurological conditions such as Alzheimer's disease, Lewy body dementias, and spongiform encephalopathies. This question is considered in light of our knowledge that copper-dependent enzymes are important contributors to antioxidant defense, and that the mammalian organism has robust mechanisms for maintaining constant levels of copper not only in body fluids but in its major organs. Overall,and except in unusual genetic states that lead to copper overload in specific cells (particularly those in liver), it appears that excessive intake of copper is not a significant factor in the development of disease states.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 05/2012; 733(1-2):83-91. DOI:10.1016/j.mrfmmm.2012.03.010 · 3.68 Impact Factor
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Mary Carmen Vázquez