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Wednesday, May 07, 2014

Metals in Neurodegenerative Disease

Chemical Biology and Inorganic Chemistry Seminar
1640 Chemistry
4:00 PM - 5:30 PM

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Speaker:   Ashley Bush, University of Melbourne
Abstract:   Alzheimer's disease (AD), Hungtington’s disease (HD) and Parkinson’s disease (PD) are incurable and common neurodegenerative diseases that complicate aging. Experimental therapeutic approaches that focus on the protein aggregates that typify these disorders have been disappointing in clinical trials, suggesting that the neurodegeneration is not merely due to proteinopathy. In both diseases, there is a severe dysregulation of metal homeostasis in affected brain tissue, with iron and zinc elevation and copper depletion reported in cortex (AD) and nigra (PD), and iron and copper elevation in the caudate in HD. This is important because iron accumulation in particular causes oxidative damage, which characterizes all three diseases. We have determined that the major proteins implicated AD and PD have important functions in metal transport, and may be components of a novel metal regulatory system that fails in aging. The amyloid protein precursor facilitates the export of iron from neurons and prevents dietary iron overload from collecting within the brain. Presenilins foster the uptake of copper and zinc, and tau impacts on iron export by trafficking APP to the cell surface. Failure of the metal transport functions of these proteins may explain why metals collect within the protein aggregates that typify these disorders, and may contribute to neuronal dysfunction. Small molecules, such as PBT2, which correct the abnormalities of metal transport have been effective in animal models of these diseases, and are being tested in clinical trials.