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The Pathogenic A116V Mutation Enhances Ion-Selective Channel Formation by Prion Protein in Membranes.

ABSTRACT: Prion diseases are a group of fatal neurodegenerative disorders that afflict mammals. Misfolded and aggregated forms of the prion protein (PrP(Sc)) have been associated with many prion diseases. A transmembrane form of PrP favored by the pathogenic mutation A116V is associated with Gerstmann-Sträussler-Scheinker syndrome, but no accumulation of PrP(Sc) is detected. However, the role of the transmembrane form of PrP in pathological processes leading to neuronal death remains unclear. This study reports that the full-length mouse PrP (moPrP) significantly increases the permeability of living cells to K(+), and forms K(+)- and Ca(2+)-selective channels in lipid membranes. Importantly, the pathogenic mutation A116V greatly increases the channel-forming capability of moPrP. The channels thus formed are impermeable to sodium and chloride ions, and are blocked by blockers of voltage-gated ion channels. Hydrogen-deuterium exchange studies coupled with mass spectrometry (HDX-MS) show that upon interaction with lipid, the central hydrophobic region (109-132) of the protein is protected against exchange, making it a good candidate for inserting into the membrane and lining the channel. HDX-MS also shows a dramatic increase in the protein-lipid stoichiometry for A116V moPrP, providing a rationale for its increased channel-forming capability. The results suggest that ion channel formation may be a possible mechanism of PrP-mediated neurodegeneration by the transmembrane forms of PrP.

SUBMITTER: Sabareesan AT

PROVIDER: S-EPMC4850347 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Electrical signaling allows communication within and between different tissues and is necessary for the survival of multicellular organisms. The ionic transport that underlies transmembrane currents in cells is mediated by transporters and channels. Fast ionic transport through channels is typically modeled with a conductance-based formulation that describes current in terms of electrical drift without diffusion. In contrast, currents written in terms of drift and diffusion are not as widely used in the literature in spite of being more realistic and capable of displaying experimentally observable phenomena that conductance-based models cannot reproduce (e.g. rectification). The two formulations are mathematically related: conductance-based currents are linear approximations of drift-diffusion currents. However, conductance-based models of membrane potential are not first-order approximations of drift-diffusion models. Bifurcation analysis and numerical simulations show that the two approaches predict qualitatively and quantitatively different behaviors in the dynamics of membrane potential. For instance, two neuronal membrane models with identical populations of ion channels, one written with conductance-based currents, the other with drift-diffusion currents, undergo transitions into and out of repetitive oscillations through different mechanisms and for different levels of stimulation. These differences in excitability are observed in response to excitatory synaptic input, and across different levels of ion channel expression. In general, the electrophysiological profiles of membranes modeled with drift-diffusion and conductance-based models having identical ion channel populations are different, potentially causing the input-output and computational properties of networks constructed with these models to be different as well. The drift-diffusion formulation is thus proposed as a theoretical improvement over conductance-based models that may lead to more accurate predictions and interpretations of experimental data at the single cell and network levels.

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The Pathogenic A116V Mutation Enhances Ion-Selective Channel Formation by Prion Protein in Membranes.

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