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 norm al cellular isoform of prion protein (PrPc) to an abnormal pathologic scrap ie isoform. (PrPSc). The conversion of this single polypeptide chain involv es a reduction in the alpha -helices and an increase in beta -sheet content . This change in the content ratio of alpha -helices to beta -sheets may ex plain the diversity in the proposed mechanisms of action. Many of the patho genic properties of PrPSc, such as neurotoxicity, proteinase-resistant prop erties and induction of hypertrophy and proliferation of astrocytes, have b een attributed to the peptide fragment corresponding to residues 106-126 of prion (PrP[106-126]). In particular, the amyloidogenic and hydrophobic cor e AGAAAAGA has been implicated in modulation of neurotoxicity and the secon dary structure of PrP[106-126]. Because of some similarities between the pr operties of PrP[106-126] and PrPSc, the former is used as a useful tool to characterize the pharmacological and biophysical properties of PrPSc in gen eral 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 com plete equivalent to PrPSc in function. Several hypotheses have been propose d to explain prion-induced neurodegenerative diseases. These non-exclusive hypotheses include: (i) changes in the membrane microviscosity; (ii) change s in the intracellular Ca2+ homeostasis; (iii) superoxide dismutase and Cu2 + homeostasis; and (iv) changes in the immune system. The prion-induced mod ification 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 c hanges in Ca2+ homeostasis that further augment the abnormal electrical act ivity and the distortion of signal transduction causing cell death. It is c oncluded that the hypothesis of the interaction of PrP[106-126] with membra nes and formation of redox-sensitive and pH-modulated heterogeneous ion cha nnels is consistent with: (a) PrP-induced changes in membrane fluidity and viscosity; (b) PrP-induced changes in Ca2+ homeostasis (and does not exclud e changes in endogenous Ca2+ transport pathways and Cu2+ homeostasis); (c) PrP role as an antioxidant; and (d) the PrP structural properties, i.e. bet a sheets, protein aggregation, hydrophobicity, functional significance of s pecific amino acids (e.g. methionine, histidine) and regulation with low pH . (C) 2001 Elsevier Science Ireland Ltd. An rights reserved.