Although cell lines and in animal models of prion

Although PrPC is known to be present as a
GPI-anchored extracellular protein, the GPI-anchor status of misfolded prion
protein remains unclear (Puig et al., 2014). Moreover, the
role of the GPI-anchor in prion protein misfolding, and in aggregates mediating
neurotoxicity remains unclear. It should be pointed out that most of the in vitro toxicity and infectivity
experiments are carried out with prion protein lacking a GPI anchor. Cytosolic
PrP, which does not have the GPI anchor, has also been shown to cause
neurodegenerative features, in the absence of any significant accumulation of
PrPSc, in both cultured neuronal cell lines and in animal models of
prion disease (Ma et al., 2002; Thackray et al., 2014). It appears that alternative
forms of PrP, both soluble and membrane-attached, which are different from PrPSc
in both structural and biochemical properties, may have important roles in
prion-mediated neurodegeneration (Biasini et al., 2012). Anchorless prion protein
expression has been shown to cause brain damage in transgenic mice (Chesebro et al., 2005). Moreover, PrP can be “shed” from the cell
surface upon cleavage, either within the protein or at the linkage to the GPI
anchor, under physiological conditions (Taylor et al., 2009; Altmeppen et al., 2013; Liu et al., 2017).

Many
studies have utilized PrPC to study the importance of the GPI-anchor
in prion protein misfolding and aggregation, and prion diseases. Several
pathogenic mutations are found in the middle hydrophobic region, and most of
these mutations cause the GSS syndrome (Mead, 2006). Several
studies have reported the effects of these NTR mutations. The A116V mutation was
shown to facilitate the formation of the transmembrane PrP, which leads to
neurodegeneration without any detectable amount of PrPSc (Stewart et al., 2005; Faris et al., 2017). Several studies of have shown
that the expression of deletion variants of PrPC or of pathogenic
mutations present in the NTR induces spontaneous inward currents at negative
potentials (Solomon et al., 2010a; Solomon et al., 2010b). An in vivo study of both the G113V and
A116V mutant variants has reported that these mutations lead to the formation
of a highly neurotoxic protease-sensitive PrP conformation (Coleman et al., 2014). Recently, the A116V
mutation in mouse PrP without the GPI-anchor has been shown to enhance the
membrane interaction ability of the prion protein, leading to the formation of ion-selective
channels (Sabareesan et al., 2016).

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