abnormal brain iron homeostasis in human and animal prion disorders异常脑铁体内平衡人类和动物朊病毒疾病.pdfVIP

Abnormal Brain Iron Homeostasis in Human and Animal Prion Disorders 1. 1. 1. 1 1 1 Ajay Singh , Alfred Orina Isaac , Xiu Luo , Maradumane L. Mohan , Mark L. Cohen , Fusong Chen , 1 2 1 Qingzhong Kong , Jason Bartz , Neena Singh * 1 Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America, 2 Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America Abstract Neurotoxicity in all prion disorders is believed to result from the accumulation of PrP-scrapie (PrPSc), a b-sheet rich isoform of a normal cell-surface glycoprotein, the prion protein (PrPC). Limited reports suggest imbalance of brain iron homeostasis as a significant associated cause of neurotoxicity in prion-infected cell and mouse models. However, systematic studies on the generality of this phenomenon and the underlying mechanism(s) leading to iron dyshomeostasis in diseased brains are lacking. In this report, we demonstrate that prion disease–affected human, hamster, and mouse brains show increased total and redox-active Fe (II) iron, and a paradoxical increase in major iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) at the end stage of disease. Furthermore, examination of scrapie-inoculated hamster brains at different timepoints following infection shows increased levels of Tf with time, suggesting increasing iron deficiency with disease progression. Sporadic Creutzfeldt-Jakob disease (sCJD)–affected human brains show a similar increase in total iron and a direct correlation between PrP and Tf levels,