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 Zn²⁺ or Cu²⁺ 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 Zn²⁺ or Cu²⁺. Carnosine (β-alanyl histidine) significantly inhibited both the β-sheet formation and the neurotoxicity of PrP106-126. Our results suggested that Zn²⁺ and Cu²⁺ 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.