The long term of this study is to provide detailed mechanistic understanding of Wilson's disease (WD). WD is a severe and potentially fatal human disorder of copper homeostasis, caused by mutations in the copper transporter ATP7B. The disease is associated with copper overload in tissues, particularly in the liver, and a wide spectrum of hepatic, neurologic, and psychiatric abnormalities. Currently, specific molecular pathways through which copper triggers WD are poorly understood. The proposed studies will use a multidisciplinary approach based on modern methodologies to identify biochemical and cellular events that lead to the onset and progression of WD. The experiments measuring oxidation state of glutathione and proteins will determine whether in WD copper acts by modifying the redox environment of cellular compartments (Specific Aim 1). The role of hnRNP A2 in cell response to copper overload will be determined by characterizing its intracellular localization, interacting proteins, and a subset of transcripts affected by hnRNPA2 up-regulation (Specific Aim 2). Metabolic changes in the brain of Atp7b-/- mice will be characterized by corelating time-dependent copper distribution with changes in lipids and mRNA profiles at different stages of the disease (Specific Aim 3). Cell injury and behavior changes will be evaluated in conjunctions with analysis of molecular and metabolic changes.
The project focuses on elucidating the mechanisms of pathology development in Wilson's disease, a severe genetic disorder in humans with hepatic and neurologic manifestations. The studies will identify key molecular factors and proceses that underlie the development and progresion of pathologic changes in Wilson's disease. The results will contribute to improvement of diagnostic and treatment of this potentially fatal disorder of copper metabolism.
| Schmidt, Katharina; Ralle, Martina; Schaffer, Thomas et al. (2018) ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine-?-hydroxylase. J Biol Chem 293:20085-20098 |
| Reed, Emily; Lutsenko, Svetlana; Bandmann, Oliver (2018) Animal models of Wilson disease. J Neurochem 146:356-373 |
| Muchenditsi, Abigael; Yang, Haojun; Hamilton, James P et al. (2017) Targeted inactivation of copper transporter Atp7b in hepatocytes causes liver steatosis and obesity in mice. Am J Physiol Gastrointest Liver Physiol 313:G39-G49 |
| Lutsenko, Svetlana (2016) Copper trafficking to the secretory pathway. Metallomics 8:840-52 |
| Hatori, Yuta; Yan, Ye; Schmidt, Katharina et al. (2016) Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway. Nat Commun 7:10640 |
| Bhattacharjee, Ashima; Yang, Haojun; Duffy, Megan et al. (2016) The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria. J Biol Chem 291:16644-58 |
| Hatori, Yuta; Lutsenko, Svetlana (2016) The Role of Copper Chaperone Atox1 in Coupling Redox Homeostasis to Intracellular Copper Distribution. Antioxidants (Basel) 5: |
| Krishnamoorthy, Lakshmi; Cotruvo Jr, Joseph A; Chan, Jefferson et al. (2016) Copper regulates cyclic-AMP-dependent lipolysis. Nat Chem Biol 12:586-92 |
| Chesi, Giancarlo; Hegde, Ramanath N; Iacobacci, Simona et al. (2016) Identification of p38 MAPK and JNK as new targets for correction of Wilson disease-causing ATP7B mutants. Hepatology 63:1842-59 |
| Wooton-Kee, Clavia Ruth; Jain, Ajay K; Wagner, Martin et al. (2015) Elevated copper impairs hepatic nuclear receptor function in Wilson's disease. J Clin Invest 125:3449-60 |
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