The objective of this research program is to elucidate, at the molecular level, the mechanism and function of copper and zinc binding in the prion protein (PrP) and the relationship of these interactions to neuron maintenance and neurological disease. A misfolded form of the prion protein (PrP) is responsible for a class of fatal neurodegenerative diseases termed the Transmissible Spongiform Encephalopathies (TSEs), which include mad cow disease and Creutzfeldt-Jakob disease in humans. PrP is a highly abundant, membrane-bound glycoprotein found in all mammals and avian species. Although originally recognized for its role in neurodegenerative disease, it is now clear that PrP is essential for sustaining neuron function and regulating apoptosis. PrP takes up both copper and zinc at sites are essential for PrP activity. Over the last funding period, the PI's laboratory characterized structural and thermodynamic features of these metal ion sites and also identified a remarkable link between certain mutations and onset age in inherited prion disease. The next funding period will build on these findings using both magnetic resonance and cellular studies with the following projects: 1) determine the structure of the full-length, copper or zinc occupied protein;2) evaluate how metal ions influence in vivo cleavage, implicated in apoptosis regulation;and 3) examine how structure and cellular behavior is altered by mutations associated with inherited disease, and also by mutations that prevent disease. Moreover, project three will apply new synthetic strategies for investigating the role of protein glycosylation. It is anticipated that these studies will provide fundamental new concepts for understanding the role of both PrP and copper in basic neurochemistry, and strategies for treating neurodegenerative disease and brain trauma.

Public Health Relevance

This research is aimed at evaluating proteins of the central nervous system that regulate copper and other micronutrients. These proteins are essential for neuron health and understanding their behavior will lead to new strategies for treating neurodegenerative diseases, such as Alzheimer's, and treating brain trauma.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
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University of California Santa Cruz
Schools of Arts and Sciences
Santa Cruz
United States
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McDonald, Alex J; Millhauser, Glenn L (2014) PrP overdrive: does inhibition of ?-cleavage contribute to PrP(C) toxicity and prion disease? Prion 8:
McDonald, Alex J; Dibble, Jessie P; Evans, Eric G B et al. (2014) A new paradigm for enzymatic control of *-cleavage and *-cleavage of the prion protein. J Biol Chem 289:803-13
Pushie, M Jake; Nienaber, Kurt H; McDonald, Alex et al. (2014) Combined EXAFS and DFT structure calculations provide structural insights into the 1:1 multi-histidine complexes of Cu(II) , Cu(I) , and Zn(II) with the tandem octarepeats of the mammalian prion protein. Chemistry 20:9770-83
Spevacek, Ann R; Evans, Eric G B; Miller, Jillian L et al. (2013) Zinc drives a tertiary fold in the prion protein with familial disease mutation sites at the interface. Structure 21:236-46
Proukakis, Christos; Dudzik, Christopher G; Brier, Timothy et al. (2013) A novel *-synuclein missense mutation in Parkinson disease. Neurology 80:1062-4
Naab, Benjamin D; Guo, Song; Olthof, Selina et al. (2013) Mechanistic study on the solution-phase n-doping of 1,3-dimethyl-2-aryl-2,3-dihydro-1H-benzoimidazole derivatives. J Am Chem Soc 135:15018-25
Jiang, Dianlu; Zhang, Lin; Grant, Gian Paola G et al. (2013) The elevated copper binding strength of amyloid-? aggregates allows the sequestration of copper from albumin: a pathway to accumulation of copper in senile plaques. Biochemistry 52:547-56
Dudzik, Christopher G; Walter, Eric D; Abrams, Benjamin S et al. (2013) Coordination of copper to the membrane-bound form of ýý-synuclein. Biochemistry 52:53-60
Dudzik, Christopher G; Walter, Eric D; Millhauser, Glenn L (2011) Coordination features and affinity of the Cu²+ site in the ?-synuclein protein of Parkinson's disease. Biochemistry 50:1771-7
Liu, Lin; Jiang, Dianlu; McDonald, Alex et al. (2011) Copper redox cycling in the prion protein depends critically on binding mode. J Am Chem Soc 133:12229-37

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