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Elevated copper remodels hepatic RNA processing machinery in the mouse model of Wilson's disease.

ABSTRACT: Copper is essential to mammalian physiology, and its homeostasis is tightly regulated. In humans, genetic defects in copper excretion result in copper overload and Wilson's disease (WD). Previous studies on the mouse model for WD (Atp7b(-)(/-)) revealed copper accumulation in hepatic nuclei and specific changes in mRNA profile prior to the onset of pathology. To find a molecular link between nuclear copper elevation and changes in hepatic transcriptome, we utilized quantitative ionomic and proteomic approaches. X-ray fluorescence and inductively coupled plasma mass spectrometry analysis indicate that copper in the Atp7b(-/-) nucleus, while highly elevated, does not markedly alter nuclear ion content. Widespread protein oxidation is also not observed, although the glutathione reductase SelH is upregulated, likely to maintain redox balance. We further demonstrate that accumulating copper affects the abundance and/or modification of a distinct subset of nuclear proteins. These proteins populate pathways that are most significantly associated with RNA processing. An alteration in splicing pattern was observed for hnRNP A2/B1, itself the RNA shuttling factor and spliceosome component. Analysis of hnRNP A2/B1 mRNA and protein revealed an increased retention of exon 2 and a selective 2-fold upregulation of a corresponding protein splice variant. Mass spectrometry measurements suggest that the nucleocytoplasmic distribution of RNA binding proteins, including hnRNP A2/B1, is altered in the Atp7b(-/-) liver. We conclude that remodeling of the RNA processing machinery is an important component of cell response to elevated copper that may guide pathology development in the early stages of WD.

SUBMITTER: Burkhead JL

PROVIDER: S-EPMC3033566 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Elevated copper remodels hepatic RNA processing machinery in the mouse model of Wilson's disease.

Burkhead Jason L JL Ralle Martina M Wilmarth Phillip P David Larry L Lutsenko Svetlana S

Journal of molecular biology 20101210 1

Copper is essential to mammalian physiology, and its homeostasis is tightly regulated. In humans, genetic defects in copper excretion result in copper overload and Wilson's disease (WD). Previous studies on the mouse model for WD (Atp7b(-)(/-)) revealed copper accumulation in hepatic nuclei and specific changes in mRNA profile prior to the onset of pathology. To find a molecular link between nuclear copper elevation and changes in hepatic transcriptome, we utilized quantitative ionomic and prote ...[more]

PMID: 21146535

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Project description:Background and purposeWilson's disease (WD), also known as hepatoleticular degeneration (HLD), is a rare autosomal recessive genetic disorder of copper metabolism, which causes copper to accumulate in body tissues. In this study, rats fed with copper-laden diet are used to render the clinical manifestations of WD, and their copper toxicity-induced organ lesions are studied. To investigate metabolic behaviors of 'decoppering' process, penicillamine (PA) was used for treating copper-laden rats as this chelating agent could eliminate excess copper through the urine. To date, there has been limited metabolomics study on WD, while metabolic impacts of copper accumulation and PA administration have yet to be established.Materials and methodsA combination of 1HNMR spectroscopy and multivariate statistical analysis was applied to examine the metabolic profiles of the urine and blood serum samples collected from the copper-laden rat model of WD with PA treatment.ResultsCopper accumulation in the copper-laden rats is associated with increased lactate, creatinine, valine and leucine, as well as decreased levels of glucose and taurine in the blood serum. There were also significant changes in p-hydroxyphenylacetate (p-HPA), creatinine, alpha-ketoglutarate (α-KG), dimethylamine, N-acetylglutamate (NAG), N-acetylglycoprotein (NAC) in the urine of these rats. Notably, the changes in p-HPA, glucose, lactate, taurine, valine, leucine, and NAG were found reversed following PA treatment. Nevertheless, there were no changes for dimethylamine, α-KG, and NAC as a result of the treatment. Compared with the controls, the concentrations of hippurate, formate, alanine, and lactate were changed when PA was applied and this is probably due to its side effect. A tool named SMPDB (Small Molecule Pathway Database) is introduced to identify the metabolic pathway influenced by the copper-laden diet.ConclusionThe study has shown the potential application of NMR-based metabolomic analysis in providing further insights into the molecular mechanism underlying disorder due to WD.

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Elevated copper remodels hepatic RNA processing machinery in the mouse model of Wilson's disease.

Publications

Elevated copper remodels hepatic RNA processing machinery in the mouse model of Wilson's disease.

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