title: Paradoxical role of prion protein aggregates in redox-iron induced toxicity.
abstract: BACKGROUND
  Imbalance of iron homeostasis has been reported in sporadic Creutzfeldt-Jakob-disease (sCJD) affected human and scrapie infected animal brains, but the contribution of this phenotype to disease associated neurotoxicity is unclear.
  
  
  RESULTS
  Using cell models of familial prion disorders, we demonstrate that exposure of cells expressing normal prion protein (PrP(C)) or mutant PrP forms to a source of redox-iron induces aggregation of PrP(C) and specific mutant PrP forms. Initially this response is cytoprotective, but becomes increasingly toxic with time due to accumulation of PrP-ferritin aggregates. Mutant PrP forms that do not aggregate are not cytoprotective, and cells show signs of acute toxicity. Intracellular PrP-ferritin aggregates induce the expression of LC3-II, indicating stimulation of autophagy in these cells. Similar observations are noted in sCJD and scrapie infected hamster brains, lending credence to these results. Furthermore, phagocytosis of PrP-ferritin aggregates by astrocytes is cytoprotective, while culture in astrocyte conditioned medium (CM) shows no measurable effect. Exposure to H(2)O(2), on the other hand, does not cause aggregation of PrP, and cells show acute toxicity that is alleviated by CM.
  
  
  CONCLUSIONS
  These observations suggest that aggregation of PrP in response to redox-iron is cytoprotective. However, subsequent co-aggregation of PrP with ferritin induces intracellular toxicity unless the aggregates are degraded by autophagosomes or phagocytosed by adjacent scavenger cells. H(2)O(2), on the other hand, does not cause aggregation of PrP, and induces toxicity through extra-cellular free radicals. Together with previous observations demonstrating imbalance of iron homeostasis in prion disease affected brains, these observations provide insight into the mechanism of neurotoxicity by redox-iron, and the role of PrP in this process.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Dola
authors.initials: D
authors.lastname: Das
authors.forename: Xiu
authors.initials: X
authors.lastname: Luo
authors.forename: Ajay
authors.initials: A
authors.lastname: Singh
authors.forename: Yaping
authors.initials: Y
authors.lastname: Gu
authors.forename: Soumya
authors.initials: S
authors.lastname: Ghosh
authors.forename: Chinmay K
authors.initials: CK
authors.lastname: Mukhopadhyay
authors.forename: Shu G
authors.initials: SG
authors.lastname: Chen
authors.forename: Man-Sun
authors.initials: MS
authors.lastname: Sy
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Kong
authors.forename: Neena
authors.initials: N
authors.lastname: Singh
mesh_terms: D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology*; D005293:Ferritins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008854:Microscopy, Electron; D010587:Phagocytosis / Q000187:drug effects; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*
chemical_list: D017077:Culture Media, Conditioned; D005290:Ferric Compounds; D011328:Prions; D000644:Quaternary Ammonium Compounds; D005293:Ferritins; D006861:Hydrogen Peroxide; C013531:ferric ammonium citrate