Prion diseases can occur spontaneously, by
infection, or by hereditary mutations, but the common connection between all
prion diseases is the misfolded state of prion (Cohen and
Prusiner, 1998; Collinge,
2001; Aguzzi et al., 2008a). A large number of prion disease
cases appear spontaneously (? 85 %), or are transmitted from individuals
infected with prion diseases (? 5%). Nevertheless, a significant number (? 10
%) of hereditary (familial) forms of prion diseases, due to specific mutations
in the Prnp gene, have been reported
in humans and other mammals (Mead, 2006). Mutations in
the Prnp gene that are associated
with prion diseases can be broadly divided into two categories: mutations that
cause changes in the protein and induce prion diseases, and mutations that
prevent prion disease propagation (Jones et al., 2006; Aguzzi et al., 2008a; Van der Kamp and Daggett, 2009; Coleman et al., 2014; Asante et al.,
2015; Singh and
Udgaonkar, 2015; Sabareesan
and Udgaonkar, 2016; Sabareesan and Udgaonkar, 2017). Despite the fact that pathogenic
mutations show different effects on PrP, 
it is very unlikely that TSEs are induced by the loss of functional PrPC
due its misfolding, because mice devoid of PrPC do not show
neurodegeneration (Büeler et al., 1993). Hence, it is
possible that TSEs are caused by a gain of toxic function due to the formation
of PrPSc.

            In some, but not all, prion diseases,
the formation and accumulation of the pathological form of the prion protein,
PrPSc is seen (Collinge,
2001; Aguzzi and
Polymenidou, 2004; Aguzzi et al., 2008a). The progressive accumulation of
PrPSc in certain prion diseases is known to correlate with the
extent of severity of the disease (Prusiner et al., 1983; Caughey et al., 2009; Laurén et al.,
2009). It appears that there is a strong
correlation between prion protein misfolding and TSEs. However, increasing evidence suggests that misfolding
and aggregation of PrP is an important, but not a sufficient factor in prion disease
aetiology. Although PrPSc is well established as the infectious
form, it might not be the direct cause of neurodegeneration, at least in some
prion diseases. Several disease-linked mutations in
animals do not result in any accumulation of such amyloid plaques (Nitrini et al., 1997; Hegde et al., 1998; Coleman et al.,
2014). For example, it has been reported
that the A116V mutation facilitates the formation of a transmembrane form of
PrP, which leads to neurodegeneration without any detectable accumulation of
PrPSc (Hegde et al., 1998).

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Despite
the clear understanding about the presence of these two species, PrPC
and misfolded prion protein, the mechanism of conformational conversion, as
well as the final structure of the misfolded prion protein remain unclear. Although
the structure of PrPC is well known, the structure of PrPSc
remains poorly defined. A detailed structural understanding of the misfolded,
aggregated, protease-resistant PrPSc is therefore essential. In vitro studies of prion protein
misfolding and aggregation invariably utilize recombinant PrP (PrP).

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