In the in vivo generated PrPSc. Although many studies

In many amyloid diseases, the disease
pathology is associated mostly with the gain of toxic function, rather than with
the loss of normal functional protein (Ballatore et al., 2007; Winklhofer et al., 2008; Olzscha et al.,
2011). The toxic oligomer hypothesis of
amyloid disease suggests that the oligomeric protein assemblies, formed from
non-toxic proteins, are responsible for the toxic gain of function (Caughey and
Lansbury, 2003; Kayed et al., 2003; Silveira et al., 2005; Glabe and Kayed, 2006; Caughey et al.,
2009). In many neurodegenerative
diseases, including prion diseases, pre-fibrillar aggregates, as opposed to
mature amyloid fibrils, are considered responsible for the neurotoxicity (Caughey and
Lansbury, 2003; Ferreira et al., 2007). Moreover, it has been shown that
the most infectious structures for the prion protein are small oligomers (Silveira et al., 2005). Pre-fibrillar aggregates
made in vitro from both PrPC
and PrP have been shown to be cytotoxic, and to spread disease in healthy
animals (Legname et al., 2004; Castilla et al., 2005; Novitskaya et
al., 2006; Wang et al., 2010; Miller et al., 2013). However, it is important to point
out that these in vitro generated
aggregates are not as infectious as the in
vivo generated PrPSc.   

           Although
many studies have shown the significance of amyloid conformations of proteins
in neurodegenerative disorders, the molecular properties of the pathogenic species,
and the mechanism by which protein aggregates induce cell damage remain unclear
(Thompson and
Barrow, 2002; Caughey and
Lansbury, 2003). Increasing evidence indicates
that the toxicity of misfolded prion protein is directly correlated with the ability
to interact with, and to disrupt, lipid membranes, thereby perturbing the ionic
homeostasis of a cell (Wang et al., 2006; Caughey et al., 2009; Singh et al.,
2012; Singh et al., 2014; Sabareesan et al., 2016). Indeed, amyloid oligomers formed from
several different proteins can permeabilize lipid bilayers and cellular
membranes, suggesting that this might be the primary toxic mechanism of amyloid
pathogenesis (Caughey and
Lansbury, 2003; Demuro et al., 2005; Quist et al., 2005; Butterfield and Lashuel, 2010).

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           In the case of the prion protein, it
has been shown that peptides derived from sequence segments 82-146,
105-126, and 185-206, have the capability to form ion channels (Lin et al., 1997; Bahadi et al., 2003; Kagan et al.,
2004; Quist et al., 2005; Alier et al., 2010). Recent studies have
shown that pre-fibrillar
aggregates of PrP can disrupt lipid membrane structures (Singh et al.,
2012; Singh et al., 2014), suggesting that such disruption may be the mechanism of
prion protein mediated neurotoxicity (Figure 3). The prion
protein can also assemble in the membrane and form specific channels (Sabareesan et al., 2016). Similarly, in
eukaryotes, it has been shown that pro-apoptotic members of the Bcl-2 family assemble
into oligomers that form non-specific channels in the target mitochondrial
membrane (Antonsson et al., 2000). In many cases,
protein insertion into the plasma membrane of the target cell requires a
conformational change leading to changes in its secondary structural elements. It
is not clear, however, if the structural changes in the Bcl-2 family proteins (Chipuk and
Green, 2008), as well as the
pore-forming toxins (Dal Peraro
and Van Der Goot, 2016) and are
equivalent to those in the case of pre-fibrillar aggregates of PrP (Lashuel and
Lansbury, 2006) (Figure 4).