Abstract
The interactions of transition metals with the prion protein (PrP) are well-documented and characterized, however, there is no consensus on their role in either the physiology of PrP or PrP-related neurodegenerative disorders. PrP has been reported to protect cells from the toxic stimuli of metals. By employing a cell viability assay, we examined the effects of various concentrations of Cu2+, Zn2+, Mn2+, and Co2+ on Zpl (Prnp -/-) and ZW (Prnp +/+) hippocampus-derived mouse neuronal cells. Prnp -/- Zpl cells were more sensitive to all four metals than PrP-expressing Zw cells. However, when we introduced PrP or only the empty vector into Zpl cells, we could not discern any protective effect associated with the presence of PrP. This observation was further corroborated when assessing the toxic effect of metals by propidium-iodide staining and fluorescence activated cell sorting analysis. Thus, our results on this mouse cell culture model do not seem to support a strong protective role for PrP against transition metal toxicity and also emphasize the necessity of extreme care when comparing cells derived from PrP knock-out and wild type mice.
Highlights
Transmissible spongiform encephalopathies (TSEs) or prion diseases are a family of rare and fatal neurodegenerative disorders that affect humans and many other mammals
The molecular pathogenesis of TSEs is still not well understood, it is widely accepted that the conformational transition of the native and predominantly α-helical cellular prion protein (PrPC) to a β-sheet rich pathogenic scrapie isoform (PrPSc) that results in the accumulation of PrPSc aggregates is the central step/event of the diseases
While some Prnp−/− cells are generated from mice with the ectopic expression of Doppel in the central nervous system (CNS) [63,67], Kim and coworkers have established a series of hippocampal neuronal cell lines from Zürich I Prnp−/− mice along with their respective controls from the ICR Prnp+/+ mice [63]
Summary
Transmissible spongiform encephalopathies (TSEs) or prion diseases are a family of rare and fatal neurodegenerative disorders that affect humans and many other mammals They include Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia and kuru in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep [1,2,3]. These diseases are some of the most typical representatives of conformational diseases, which include for example Alzheimer’s disease, Parkinson’s diseases, type 2 diabetes, amyloidosis, several forms of triplet repeat diseases, and dementia with Lewy bodies [4,5]. The cellular isoform, PrPC is implicated in other conformational diseases where it might serve as a cell surface receptor for protein aggregates most importantly for β-amyloid oligomers [6]
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