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 alpha-helices and an increase in beta-sheet content. This change in the content ratio of alpha-helices to beta-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 Ca(2+) homeostasis; (iii)
superoxide dismutase and Cu(2+) homeostasis; and (iv) changes in the immune system. The
prion-induced modification in Ca(2+) homeostasis is the result of: (1)
prion interaction with intrinsic ion transport
proteins, e.g. L-type Ca(2+) channels in the surface membrane, and IP(3)-modulated Ca(2+) channels in the internal membranes, and/or (2) formation of
cation channels. These two mechanisms of action lead to changes in Ca(2+) 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 Ca(2+) homeostasis (and does not exclude changes in endogenous Ca(2+) transport pathways and Cu(2+) homeostasis); (c) PrP role as an
antioxidant; and (d) the PrP structural properties, i.e. beta sheets,
protein aggregation, hydrophobicity, functional significance of specific
amino acids (e.g.
methionine,
histidine) and regulation with low pH.