The long-term goal of this project is to understand the fundamental mechanisms that regulate human copper (Cu) homeostasis in the central nervous system. Cu is essential for numerous physiologic processes, including myelination of neurons, immune response, catecholamines balance, mitochondria respiration, and protection against oxygen radicals. Disrupted Cu homeostasis causes or significantly contributes to the pathogenesis of several neurodegenerative disorders including Menkes disease, Wilson disease, MEDNIK syndrome, and Alzheimer's disease. The molecular mechanisms that govern Cu homeostasis in most cells of the central nervous system, especially during metabolic changes, are greatly understudied and poorly understood. This project will feel the information gap by characterizing the biochemical mechanisms of Cu transport and utilization in noradrenergic neurons (NEN) of locus coeruleus. The experiments will determine specific roles of the two Cu-transporting ATPases (Cu-ATPase) ATP7A and ATP7B in the maintenance of the cytosolic Cu balance in these neurons and in activation of dopamine-?-hydroxylase (DBH), the key enzyme involved in biosynthesis of norepinephrine. The studies will also characterize the NEN-specific regulatory mechanisms that coordinate the Cu-ATPases activity with DBH secretion. The research program has three specific aims. Experiments under Aim 1 will elucidate how ATP7A, ATP7B and the Cu chaperone Atox1 work together to maintain Cu homeostasis in noradrenergic neurons. Studies under Aim 2 will determine the role of Cu- ATPases ATP7A and ATP7B in activation and secretion of dopamine-?-hydroxylase (DBH), and Aim 3 will characterize the novel feedback pathway by investigating how Cu counteracts the inhibitory effect of NE on DBH secretion. The results will help to develop new mechanistic paradigms of Cu homeostasis in the brain, contribute to understanding of Wilson disease pathogenesis, and, ultimately, help to design better treatments for disorders of Cu misbalance.
This project aims to elucidate how noradrenergic neurons of the central nervous system use the copper- transporting molecules to regulate activity and secretion of dopamine-?-hydroxylase, an essential enzyme involved in the biosynthesis of norepinephrine. The results will help to understand the role of copper in the pathophysiology of neurodegenerative disorders, including Menkes disease, Wilson disease, and Parkinson's disease, and facilitate the development of better treatments for the disorders of copper misbalance.
| 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 |
| 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 |
| 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: |
| 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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