Wilson disease (WD) is a severe metabolic disorder associated with copper accumulation in several tissues and marked hepatic, neurological, and/or psychiatric abnormalities. The disease is caused by mutations in the gene ATP7B, which encodes the copper-transporting P-type ATPase, or Wilson disease protein (WNDP). Recent studies have begun to uncover the biochemical and cell biological properties of WNDP; however, the detailed information on molecular mechanisms of copper-induced pathology is still lacking. Our laboratory has recently demonstrated that genetically engineered Atp7b-/- knock-out mice recapitulate many symptoms of WD and represent a valuable animal model for characterization of this human disorder. We have also established that at the early stages of the disease copper accumulates in the nuclei of Atp7b-/- hepatocytes, triggering changes in gene expression and overall nuclear morphology. The molecular mechanism of these important early events is unknown and will be investigated in this study. Currently, no information is available on the role of copper in mammalian nuclei, and proteins that bind nuclear copper or proteins regulated by intra-nuclear copper remain unidentified. This information is central for understanding of the effects of copper on liver nuclear proteome, and it will be obtained in this study using modern biochemical approaches.
Three aims are proposed. First, to test the hypothesis that copper accumulation induces specific changes in nuclear proteome using quantitative gel-electrophoresis and mass-spectrometry. Second, to identify nuclear proteins that show change in abundance and posttranslational modification in response to copper accumulation. Third, to identify proteins involved in binding of copper in normal and diseased nuclei. The studies will yield the first quantitative data on the role of copper in mammalian nuclei and yield key information on biochemical steps involved in the early stages of WD pathology. The proteomic information and methodology generated during this study will be applicable for analysis of other hepatic disorders in humans. ? ? ?
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