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Prion diseases are fatal neurodegenerative diseases, including Creutzfeldt-Jacob disease in humans, scrapie in sheep and bovine spongiform encephalophaty or "mad cow" disease, characterized by neuronal loss and accumulation of abnormal prion protein (PrPSc). The mechanisms leading to neurodegeneration and cell death are not known, but it has been recently shown that there is an elevated iron content and iron-induced oxidative stress in the brains of scrapie-infected animals. The aim of the current research project is to study iron regulation and oxidative stress in scrapie-infected neuroblastoma cells, and possible involvement of the changed iron metabolism in the pathogenesis of prion diseases. We are specifically interested in the characterization of the expression and regulation of NifS, an enzyme involved in the biogenesis of cellular iron-sulfur proteins, in scrapie infected cells since the dysregulation of iron-sulfur protein biosynthesis has been shown to lead to abnormal iron sensing in mitochondria and increased oxidative stress. The applicant has earlier cloned the nifs cDNA from human cells and shown that the single mRNA of nifs gives rise to at least two forms of NifS proteins localized to mitochondria and cytosol or nucleus. Studies in yeast cells have shown that the down-regulation of NifS expression results in abnormal high iron levels in mitochondria, lower iron-sulfur cluster biosynthesis and elevated oxidative stress in cells. Our preliminary studies have shown that scrapie-infected mouse N2a neuroblastoma cells express about 2-fold lower amounts of NifS protein as compared to the wild-type cells. Therefore, studying mechanisms leading to the dysregulation of NifS biosynthesis and iron metabolism in prion-infected neuroblastoma cells would help us to better understand the processes leading to the pathogenesis of prion diseases and could lead to the design of drugs. |