Ion channels induced by the prion protein

Abstract

Prion diseases comprise a group of rapidly progressive and invariably fatal neurodegenerative disorders for which there are no effective treatments. While conversion of the cellular prion protein (PrP(C)) to a β-sheet rich isoform (PrP(Sc) ) is known to be a critical event in propagation of infectious prions, the identity of the neurotoxic form of PrP and its mechanism of action remain unclear. Insights into this mechanism have been provided by studying PrP molecules harboring deletions and point mutations in the conserved central region, encompassing residues 105-125. When expressed in transgenic mice, PrP deleted for these residues (Δ105-125) causes a spontaneous neurodegenerative illness that is reversed by co-expression of wild-type PrP. In cultured cells, Δ105-125 PrP confers hypersensitivity to certain cationic antibiotics and induces spontaneous ion channel activity that can be recorded by electrophysiological techniques. We have utilized these drug-hypersensitization and current-inducing activities to identify which PrP domains and subcellular locations are required for toxicity. We present an ion channel model for the toxicity of Δ105-125 PrP and related mutants and speculate how a similar mechanism could mediate PrP(Sc)-associated toxicity. Therapeutic regimens designed to inhibit prion-induced toxicity, as well as formation of PrP(Sc) , may prove to be the most clinically beneficial.

Cytoprotective and toxic functions of the prion protein family

“…PrPCR and several other HD mutants have also been found to cause spontaneous inward ionic currents through the plasma membranes of various cell types (39,40), which activities were observed also by PrP-s harbouring familiar TSE-related point mutations. These effects, although not being directly toxic, were also abrogated by the co-expression of WT PrP.…”

“…The most obvious phenotype associated with the Shmerling or CR mutations in PrP-s in cell models is the drug hypersensitivity and the occurrence of spontaneous inward cationic currents (37,39). Strong evidence supports that the same functional changes of PrPCR is behind these two phenotypes detected in different models (40).…”

“…The PrP CC1 was described to be able to bind glycosaminoglycans (GAGs) and also act as a protein transduction domain (PTD) (40,99). Based on their previous findings of drug hypersensitivity and spontaneous ionic currents, and the PTD activity of the CC1 domain, the Harris-group proposed a model where PrPCR is able to form transmembrane pores, through which such elevated uptake of drugs and spontaneous inward cationic currents may occur (40,99).…”

“…Relation with neurodegeneration occurring in TSE-s A handful PrP variants harbouring certain familial GSS or CJD-related point mutations in the CC2 or HD exhibit both of the drug sensitizing and ionic current generating activities (39,40). One of them is P101L, the mouse variant of the most common GSS-causing mutation of human PrP (P102L PrP) (101).…”

Investigation of the role of prion protein in protection against transition metal induced toxicity

“…The direct or indirect interactions of PrP with various transition metals has been implicated in both TSE and Alzheimer's, as being a contributing factor for triggering a neurodegenerative condition (Ayton et al, 2013;Rana et al, 2009;Solomon et al, 2012 (Jackson et al, 2001b;Pandey et al, 2010;Russo et al, 2011;Singh et al, 2010;Stöckel et al, 1998). Majority of the earlier hypotheses about the normal cellular function of PrP C , addressed the protein as a Cu 2+ -binding protein (Brown et al, 1997c).…”