title: Copper (II) promotes the formation of soluble neurotoxic PrP oligomers in acidic environment.
abstract: Prion diseases are classically considered to be "amyloid diseases" caused by the deposition of amyloid fibrils in the brain. Recent studies identified soluble oligomers of PrP (prion protein) in damaged neuronal tissue. However, the details of PrP oligomerization are still unclear. In this study, we demonstrate that Cu(2+) plays a vital role in the formation of soluble PrP oligomers. A Cu(2+)-triggered structural conversion of PrP (90-231) to a β-sheet isoform in pH 5.0 buffer was revealed by circular dichroism spectra and fluorescence measurement. Soluble oligomers were isolated by size exclusion chromatography from experimental solutions, allowing atomic force microscopy to reveal their morphology. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays demonstrated that oligomeric PrP induced significant damage in and apoptosis of neuroblastoma SK-N-SH cells. These results indicate that in an acidic environment, Cu(2+) promotes the formation of neurotoxic soluble PrP oligomers.
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Centre, College of Life Sciences, Wuhan University, Wuhan 430072, PR China.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Qingying
authors.initials: Q
authors.lastname: Luo
authors.forename: Kan
authors.initials: K
authors.lastname: Luo
authors.forename: Liqin
authors.initials: L
authors.lastname: Huang
authors.forename: Wenxi
authors.initials: W
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.forename: Daiwen
authors.initials: D
authors.lastname: Pang
authors.forename: Gengfu
authors.initials: G
authors.lastname: Xiao
mesh_terms: D000143:Acids; D017209:Apoptosis; D045744:Cell Line, Tumor; D003300:Copper / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009447:Neuroblastoma / Q000473:pathology; D011328:Prions / Q000096:biosynthesis* / Q000737:chemistry / Q000633:toxicity; D011487:Protein Conformation; D055503:Protein Multimerization / Q000187:drug effects*; D012995:Solubility
chemical_list: D000143:Acids; D011328:Prions; D003300:Copper