title: Zinc, copper, and carnosine attenuate neurotoxicity of prion fragment PrP106-126.
abstract: Prion diseases are progressive neurodegenerative diseases that are associated with the conversion of normal cellular prion protein (PrP(C)) to abnormal pathogenic prion protein (PrP(SC)) by conformational changes. Prion protein is a metal-binding protein that is suggested to be involved in metal homeostasis. We investigated here the effects of trace elements on the conformational changes and neurotoxicity of synthetic prion peptide (PrP106-126). PrP106-126 exhibited the formation of β-sheet structures and enhanced neurotoxicity during the aging process. The co-existence of Zn(2+) or Cu(2+) during aging inhibited β-sheet formation by PrP106-126 and attenuated its neurotoxicity on primary cultured rat hippocampal neurons. Although PrP106-126 formed amyloid-like fibrils as observed by atomic force microscopy, the height of the fibers was decreased in the presence of Zn(2+) or Cu(2+). Carnosine (β-alanyl histidine) significantly inhibited both the β-sheet formation and the neurotoxicity of PrP106-126. Our results suggested that Zn(2+) and Cu(2+) might be involved in the pathogenesis of prion diseases. It is also possible that carnosine might become a candidate for therapeutic treatments for prion diseases.
authors: Department of Analytical Chemistry, School of Pharmaceutical Sciences Kyushu University of Health and Welfare, 1714-1 Yoshino-cho, Nobeoka-shi, Miyazaki. Japan. kawamasa@phoenix.ac.jp
authors: Masahiro
authors: M
authors: Kawahara
authors: Hironari
authors: H
authors: Koyama
authors: Tetsuya
authors: T
authors: Nagata
authors: Yutaka
authors: Y
authors: Sadakane
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D052160:Benzothiazoles; D002336:Carnosine / Q000494:pharmacology*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D002942:Circular Dichroism; D003300:Copper / Q000494:pharmacology*; D005453:Fluorescence; D006624:Hippocampus / Q000166:cytology; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D010455:Peptides / Q000737:chemistry / Q000633:toxicity; D011328:Prions / Q000737:chemistry / Q000633:toxicity*; D011487:Protein Conformation; D051381:Rats; D013844:Thiazoles / Q000378:metabolism; D014131:Trace Elements / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; D002614:Chelating Agents; D009498:Neurotoxins; D010455:Peptides; D011328:Prions; D013844:Thiazoles; D014131:Trace Elements; C009462:thioflavin T; D003300:Copper; D002336:Carnosine; D015032:Zinc