METAL IONS & PROTEIN STRUCTURE IN PROTEIN-FOLDING DISEASES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Transmissible spongiform encephalopathies are fatal neurodegenerative disorders characterized by the conversion of the normal prion protein (PrPC) into aggregates of its pathological conformer (PrPSc). The mechanism behind this structural conversion is unclear but recent studies have suggested that metal-binding is involved. The primary goal of this project is to correlate the in situ structure of prion proteins and metal-binding sites in scrapie using synchrotron-based infrared (IR) imaging and x-ray fluorescence (XRF) microprobe, respectively. To this end, we are addressing 3 specific aims: (1) How are the copper content and the PrPSc concentration correlated? Does PrPSc accumulate first, followed by decreased levels of copper? Or, does a reduction in copper concentration lead to the formation of PrPSc aggregates? (2) As the disease progresses, where do PrPSc aggregates accumulate in the tissue and how is the copper content distributed? Do the aggregates form within the neuron, or extracellularly? If they form within the neuron, are they associated with the cell membrane? (3) What is the oxidation state and structure of the metal-PrPC (and metal-PrPSc?) complex?