Mechanisms of prion-induced modifications in membrane transport properties: Implications for signal transduction and neurotoxicity

Prion-related encephalopathies are associated with the conversion of a normal cellular isoform of prion protein (PrP^c) to an abnormal pathologic scrapie isoform (PrP^Sc). The conversion of this single polypeptide chain involves a reduction in the α-helices and an increase in β-sheet content. This change in the content ratio of α-helices to β-sheets may explain the diversity in the proposed mechanisms of action. Many of the pathogenic properties of PrP^Sc, such as neurotoxicity, proteinase-resistant properties and induction of hypertrophy and proliferation of astrocytes, have been attributed to the peptide fragment corresponding to residues 106-126 of prion (PrP[106-126]). In particular, the amyloidogenic and hydrophobic core AGAAAAGA has been implicated in modulation of neurotoxicity and the secondary structure of PrP[106-126]. Because of some similarities between the properties of PrP[106-126] and PrP^Sc, the former is used as a useful tool to characterize the pharmacological and biophysical properties of PrP^Sc in general and of that domain in particular, by various laboratories. However, it is important to note that by no means can PrP[106-126] be considered a complete equivalent to PrP^Sc in function. Several hypotheses have been proposed to explain prion-induced neurodegenerative diseases. These non-exclusive hypotheses include: (i) changes in the membrane microviscosity; (ii) changes in the intracellular Ca²⁺ homeostasis; (iii) superoxide dismutase and Cu²⁺ homeostasis; and (iv) changes in the immune system. The prion-induced modification in Ca²⁺ homeostasis is the result of: (1) prion interaction with intrinsic ion transport proteins, e.g. L-type Ca²⁺ channels in the surface membrane, and IP₃-modulated Ca²⁺ channels in the internal membranes, and/or (2) formation of cation channels. These two mechanisms of action lead to changes in Ca²⁺ homeostasis that further augment the abnormal electrical activity and the distortion of signal transduction causing cell death. It is concluded that the hypothesis of the interaction of PrP[106-126] with membranes and formation of redox-sensitive and pH-modulated heterogeneous ion channels is consistent with: (a) PrP-induced changes in membrane fluidity and viscosity; (b) PrP-induced changes in Ca²⁺ homeostasis (and does not exclude changes in endogenous Ca²⁺ transport pathways and Cu²⁺ homeostasis); (c) PrP role as an antioxidant; and (d) the PrP structural properties, i.e. β sheets, protein aggregation, hydrophobicity, functional significance of specific amino acids (e.g. methionine, histidine) and regulation with low pH.