Structural to that of the aggregates generated in

Structural studies of prion protein aggregate
deposits found in vivo suggest that
the internal structure of these aggregates is similar to that of the aggregates
generated in vitro using a PrP (Merz et al., 1981; Prusiner et al., 1983; Smirnovas et al.,
2011). Amyloid fibrils formed from the
unglycosylated anchorless prion protein can be imaged using Transmission Electron
Microscopy (TEM) or Atomic Force Microscopy (AFM) (Figure 2), and these imaging
techniques have shown that these fibrillar species are typically long, straight
and unbranched polymers having a thickness of 6-10 nm, and a length of a few
microns, and are made up of a few proto-filaments (Legname et al., 2004; Bocharova et al., 2005; Anderson et al.,
2006; Sim and
Caughey, 2009; Singh and
Udgaonkar, 2013; Groveman et al., 2015; Sabareesan and Udgaonkar, 2017). A high-resolution structural
study of natural and synthetic prion protein aggregates using X-ray diffraction
methods suggested that the prion protein can form amyloid cross-? structure (Wille et al., 2009). Structural
characterization of in vitro
generated amyloid fibrils from full-length prion protein using solid-state NMR
(ssNMR) and molecular dynamics simulations indicated that a relatively small
fraction of the sequence present at the C-terminal end (173-224) of the prion
protein forms the structurally ordered amyloid core (Tycko et al., 2010; Tycko, 2011).

Studies with PrP using techniques such as
hydrogen-deuterium exchange mass spectrometry (HDX-MS) and electron
paramagnetic resonance (EPR) spectroscopy provided evidence that the C-terminal
region of the prion protein forms the structural core of the amyloid aggregates
(Cobb et al., 2007; Smirnovas et al., 2011; Singh et al.,
2012; Singh and
Udgaonkar, 2013). Several studies have also focused
on the identification of amyloidogenic sequences in the prion protein. These
structural studies of amyloid aggregates formed from different fragments of
prion protein suggest that the structural core of the prion aggregates can vary
in the sequence stretch 90 to 220 (Nguyen et al., 1995; Caughey et al., 2009). It is widely accepted that the
morphology and ultrastructural features of fibrils can vary significantly with
different scrapie forms. These features include secondary structures,
glycosylation patterns, the stability of final aggregates, as well as
conformational templating activities which can contribute to the
strain-dependent features of prion protein aggregates (Safar et al., 1998; Jones and Surewicz, 2005; Tanaka et al., 2006).

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Recent studies have challenged the classical theory that
conformational conversion of PrPC into a misfolded, insoluble,
aggregated, and protease-resistant form, PrPSc, causes
neurodegenerative diseases. These studies have indicated that
protease-sensitive, soluble, oligomeric species may be the culprit in several
prion diseases (Pastrana et al., 2006; Cronier et al., 2008; Sajnani et al.,
2012). The earliest aggregates normally
appear as spherical, or rod-like, or curvilinear structures with an approximate
diameter of 2.0-6.0 nm (Figure 2) (Simoneau et al., 2007; Jain and Udgaonkar, 2008; Caughey et al., 2009; Lindgren and Hammarström, 2010; Singh et al., 2012). Such oligomeric intermediates may
be either on-pathway or off-pathway to amyloid fibril formation (Jain and
Udgaonkar, 2008; Jain and
Udgaonkar, 2011).

Structural
and kinetic studies using NMR, HDX-MS, EPR, and FTIR show that ?2 converts into ?-sheet, and that
?1
and ?1 are unfolded in the oligomers, while the structural status of ?3 remains unclear (Cobb et al., 2007; Smirnovas et al., 2011; Singh et al.,
2012; Singh et al., 2014; Sabareesan and Udgaonkar, 2016;
Singh and Udgaonkar, 2016;
Sengupta et al., 2017). FTIR studies indicate a
significant loss of helical structure in the oligomers, and an increase in
cross-? sheet structure characteristic of amyloid structures (Sokolowski et al., 2003; Simoneau et al., 2007; Sabareesan and Udgaonkar, 2016).