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.

Energy metabolism, proteotoxic stress and age-related dysfunction – Protection by carnosine

“…These effects may help to explain how dietary carnosine helps to suppress accumulation of b-amyloid in the brains of transgenic mice model for Alzheimer's disease (Corona et al, 2011). Additionally, carnosine has recently been shown to suppress the toxicity of prion protein (Kawahara et al, 2011). This may be due to either carnosine-stimulated prion proteolysis and/or decreased glycolysis (see below), as prion proteins have also been shown to stimulate protein glycoxidation by upregulating glycolysis (Gadwinecka et al, 2010;Li et al, 2011a).…”

Disruption of Calcium Homeostasis in Alzheimer’s Disease: Role of Channel Formation by β Amyloid Protein

“…3). We have also demonstrated that PrP106-126 forms β-sheet structures and exhibits neurotoxicity as well as AβP (Kawahara et al, 2011a). In addition, oligomeric α-synuclein causes neuronal death via the Ca 2+ influx (Danzer et al, 2007).…”

Disruption of Metal Homeostasis and the Pathogenesis of Prion Diseases

“…All three peptides attenuated Cu 2+ -induced neurotoxicity [51]. Although PrP77-83 and PrP144-157 are not neurotoxic, PrP106-126 forms β-sheet structures during the "aging" process (the incubation at 37°C for several days), as determined using the thioflavin T (ThT) fluorescence assay, far-UV circular dichroism (CD) spectroscopy and atomic force microscopy (AFM) imaging.…”