Several studies have provided insights into the
formation, biophysical and biochemical characteristics, structural conversion,
as well as the mechanism of neurotoxicity of prion oligomers (Bucciantini et al., 2004; Ono et al., 2009; Fändrich, 2012). PrP oligomers exhibit neurotoxicity
and induce neuronal apoptosis under in
vivo and in vitro conditions (Caughey and
Lansbury, 2003; Simoneau et al., 2007; Campioni et al., 2010). Consequently, the focus of
research on pathological effects associated with protein aggregates has shifted
to pre-fibrillar intermediates such as oligomers. It has been observed that the
cytotoxic effects of in vitro
generated aggregates depend on the supramolecular assembly of the amyloid
aggregates, and the oligomers formed by different proteins share a common
structure, as well as mechanism of toxicity (Kayed et al., 2003; Glabe and Kayed, 2006; Caughey et al., 2009; Kayed and Lasagna-Reeves, 2013).

The toxicity induced by pre-fibrillar aggregates and
oligomers is likely to arise from the exposure of hydrophobic side chains, and
other regions in the polypeptide chains (Ross and
Poirier, 2005; Cheon et al., 2007; Caughey et al., 2009; Campioni et al.,
2010; Bemporad and
Chiti, 2012). These sites are more accessible
in the pre-fibrillar aggregates and oligomers than in either the monomer or the
fully formed amyloid fibrils. It is possible that the surface exposure of amino
acid residues enables these species to interact with a wide range of cellular
components such as the cell membrane, cellular signaling components, and
protein homeostasis machineries. Such abnormal interactions might be the
responsible for oligomer toxicity (Caughey et al., 2009; Demuro et al., 2010; Fändrich, 2012; Kayed and Lasagna-Reeves, 2013). The PrPC present on
cells has a role in mediating neurotoxic signaling via interaction with different toxic conformers of other proteins (Resenberger et al., 2011). It has been
shown that the NTR of PrPC binds to the toxic amyloid ? oligomer,
and modulates its toxic effects through an unknown mechanism (Laurén et al., 2009; Fluharty et al., 2013).

Although
pre-fibrillar species are considered as the major toxic entity, it has been
shown that fibrils and fibril fragments of some disease-linked proteins are
also equally toxic to both cultured neuronal cell lines and organisms (Novitskaya et al., 2006; Kumar et al., 2017). Despite the significant
advancement in the understanding of oligomer structure, conformational
conversion and mechanism of toxicity, the transmissibility and self-propagating
features have not been shown for these in
vitro generated PrP oligomers. It appears that these oligomers may be a
dead-end product, off-pathway to the amyloid fibril formation reaction (Jain and
Udgaonkar, 2008; Singh et al., 2014). Therefore, the formation of
amyloid deposits, which is the characteristic feature of many protein
misfolding diseases, is now considered as a pathway for the sequestration of
the toxic pre-fibrillar species (Arrasate et al., 2004; Treusch et al., 2009; Jain and Udgaonkar, 2011; Ramachandran and Udgaonkar, 2011). A detailed understanding of the size,
structure, conformation, and toxicity of protein aggregates involved in protein
misfolding diseases is critical to the elucidation of the molecular mechanisms
behind the amyloid mediated pathology.