Prions the cellular prion protein (PrPC) into

Prions are unique unconventional infectious agents lacking nucleic
acid materials. They are propagated by misfolded cellular prion proteins (PrPc)
which give rise to rare but devastating neurodegenerative diseases in humans
and animals called Prion diseases or Transmissible Spongiform Encephalopathies
(TSE).  The diseased mis-folded isoform
of prion proteins ( PrPSc) characterized by ?- sheet enrichment and
proteinase K  resistance  are thought to be the causative agent of this
rare but fatal group of neurodegenerative diseases (Byungi Jang et al.,2013).

Prion diseases affect a broad spectrum of mammals and have different
names depending on the host species, including scrapie in sheep and goats,
bovine spongiform encephalopathy (BSE) in cattle, chronic wasting diseases
(CWD) in cervids. In human the disease pathologies connected with Prion protein
are kuru, Creutzfeldt- Jacob Disease (CJD), Gerstmann Straussler- Scheinker
(GSS) and Fatal Familial Insomnia (FFI). Prion Diseases may arise spontaneously
with unknown causative agent (sporadic), be inherited (genetic) or acquired by
infection (iatrogenic), which earned it the name transmissible spongiform encephalopathies
(TSE) (Sigurdson CJ and Aguzzi A, 2007; Prusiner SB, 1996; Huang Z et al., 1995).

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The conversion of the cellular prion protein (PrPC) into
misfolded disease isoform (PrPSc) through a series of post-translationally
modification processes that aggregates in the brain of infected individual
represent the hallmark of prion disease (Oesch B et al., 1985).  Transmissible Spongiform encephalopathies are
characterized by various neurological symptoms and common histopathological
features such as spongiform degeneration of central nervous system (CNS),
astrogliosis, neuronal apoptosis and accumulation of extra cellular protein
deposits that may have or not have properties of amyloid fibrils (Y. S Kim et
al., 1990; R.I Carp et al., 1995; Westermark P et al., 2005; Chesebro B et al.,
2005; Aquzzi A, 2005; Aguzzi A and Heikenwalder M, 2006).

Although prion diseases are thought to be caused by unconventional
infectious pathogens, they possess two unique features that are shared with
other conventional infectious agents. These features are existence of multiple
prion strains and species barrier.  The
existence of multiple prion strains gives rise to different, specific and
stable disease phenotypes distinguished by clinical manifestations, incubation
time, PrPSc patterns and neuropathological features that are
faithfully maintained upon repeated passage in the same host (Prusiner SB,
1998; Collinge J, 2001; Collinge J and Clarke A.R., 2007; Cobb N.J and Surewicz
WK., 2009; Laura S. et al., 2013). Species barrier postpones the infection of a
prion across other species (Hagiwara K et al., 2013). The biological effect of
species barrier is reflected by complete resistance or low sensitivity with a
longer incubation time in some animals when inoculated with prion agents from
other species (Shi et al., 2015). Consequence of this distinct molecular
conformation results in two possible scenario when prion strain from one
species infects an animal of different species. The infectious PrPSc
may have a conformation that is not compatible with the PrPC conformation
of the host, resulting in non-conversion; in this case species barrier is
absolute and there is no disease transmission. The other possibility is that
the PrPSc conformation is compatible with the PrPC of the
host, allowing conversion and there for clinical infection. In this case the
resulting strain can be identical to the infectious strain or can change into a
different prion strain characterized by different conformation (Safar J. et
al., 1998; Tanaka M. et al., 2004).Cross species transmission of  prion agent was first demonstrated using a
sheep scrapie agent in laboratory rodents in the 1930s (Gao C. et al., 2016). The
only transmissible spongiform encephalopathy proven to have crossed a species
barrier naturally is bovine spongiform encephalopathy, which is transmitted
from cattle to human; the causative agent of variant CJD in humans (Agrimi U.
et al., 2008).

Differing opinions has been given on the likely factors responsible
for interspecies transmission of prion species. Certain groups support the
hypothesis that Interspecies transmission is possible primarily because there
is compatibility between the conformation of PrPSc of the infectious
agent and the PrPC of the new host (Bruce M. et al., 1994; Bruce ME.
Et al., 2002; Hill AF and Collinge J., 2004). Even though the primary structure
of the cellular prion protein is conserved between species, some amino acidic
residues are different resulting in PrPC with distinct molecular
conformations. Notably, ovine and murine prion protein have the same amino
acids at position 154 and 169, while bovine PrP differs only at codon 154,
having H instead of Y.  Position 154 and
159 are quite variable among mammalian prion proteins. Human and bovine
sequences are 154H-169S, sheep and goat 154Y-169S, elk and deer 145Y-169N
(Agrimi U. et al., 2008).  Others
believed apart from the homology between PrP sequences, certain unknown factors
either in the host microenvironment or the prion protein itself may directly or
indirectly be responsibility for susceptibility to prion strains during
cross-species transmission (Shi et al., 2015). Nicolas et al., (2017) from
their research findings reported that PrPC is not the sole factor
involved in the region –specific conversion of PrP. In their supplementation
experiments using homogenates prepared with brain areas from PrP knock-out
mice, they suggested the presence of region-specific modulators of PrP
conversion, other than PrPC. Timothy D. Kurt and colleagues (2017)
reported that five key residue positions markedly impacted prion conversion,
four of which were in steric zipper segments where side chains from amino acids
tightly interdigitate in a dry interface. Their findings suggested that prion
conversion between PrP sequences does not require an exact match in the side
chain between PrPC and PrPSc, nonetheless side chain
complementarity in the amyloid-prone segments is essential. Their results
supported the hypothesis that certain interspersed asparagine and glutamine
residues may facilitate the anchoring of PrPC to PrPSc through
strengthening a replicative interface, driving prion conversion between
dissimilar sequences and lowering the barrier for aggregation. Also, new
findings supports the hypothesis that sialylation of prion proteins may have
controlling effect on the rate of prion amplification and cross species
transmission (Katorcha E. et al., 2014).

Previous studies have demonstrated that infectious prion strains
can be discriminated from one another based on their differing biochemical
properties. These studies utilizes biochemical properties such as global and
/or local secondary structure (Caughey, B et al., 1998; Baron, G.S eta l.,
2011), electrophoretic mobility of protease resistance core of PrPSc,
the relative proteinase K resistance of PrPSc (Kascsak RJ et al.,
1985;  Kuczius T et al., 1999; Jacobs JG
et al., 2007), glycosylation profile, exposure of surface-exposed epitopes (
Safar J et al., 1998)  and conformational
stability as defined by resistance to denaturation by temperature and/ or
chemical agents such as Guanidine Hydrochloride ( Bett, C et al.,2013; Ayers,
J.1 et al., 2011; Peretz , D et al., 2002; Legname G  et al., 2006; Colby , D.W et al., 2009; Bett,
C et al., 2012).  A conformational
stability assay (CSA), combining guanidine hydrochloride denaturation with
limited proteolysis using Proteinase K, measures the progressive loss of PrPSc
proteinase K resistance after exposure to increasing concentration of Guanidine
Hydrochloride. It showed that different prion strains may exhibit distinct
denaturation profiles (Peretz, D et al.,2001). A conformation-dependent
immunoassay (CDI) demonstrated the existence of multiple strain –specified PrPSc
conformers by quantifying the immunoreactivity of native and denatured PrPSc
of eight hamster prion isolates and also showed that prion- infected brains
contain both protease-sensitive (sPrPSc)  and protease-resistant PrPSc (r PrPSc)
( Safar J et al., 1998,2005). Conformational Stability and Solubility Assay
(CSSA) based on differential solubility of PrPc and PrPSc measures PrPSc solubility as a
function of increased exposure to Guanidine Hydrochloride in the absence of
proteinase K, giving provision to study both protease sensitive and protease-resistant
PrPSc ( Pirisinu, L et al.,2010). 
Legname and fellow researchers, (2006) reported that a reduced resistance
to GdnHCl denaturation, indicative of a reduced conformational stability,
correlates with a shorter incubation time in mouse adapted prion strains as
less stable mice prions replicates more rapidly. Decreasing PrPSc
stability increases the fragmentation of PrPSc molecules, therefore
allowing the exposure of more PrPSc surface , which is able to bind
to PrPc , resulting in an increased rate of PrPSc formation
and hence a shortening of incubation times. In contrast, a different result was
reported for hamsters as short incubation period strains were characterized by
more stable PrPSc (Ayers, J.I et al., 2011). Also Conformational
stability has been correlated with ability of different prion strains to invade
the central nervous system (CNS). Conformationally unstable prions has been
found to be highly neuro-invasive, efficiently generate PrPSc molecules
within a short incubation period and also form diffuse, toxic non-fibrillar PrP
aggregates in the CNS hence rapidly progressing to terminal disease while more
conformationally stable prions are weakly neuro-invasive and form dense,
congophilic, fribillar plaques with mice progressing to terminal disease more
slowly (Bett C et al., 2012; Silveira  JR
et al., 2005).

Scrapie, a transmissible neurodegenerative disease in sheep and
goats is the oldest known Animal prion diseases (Shi et al., 2012). It has been
found to overcome species barriers to experimentally infect other rodents
through interspecies transmission.  Based
on incubation time, clinical manifestations, neuropathological features,
distribution of PrPSc in the central nervous system, electrophoretic
mobility and glycosylation pattern, over twenty scrapie strains serially
passaged and adapted to laboratory animals have been described till date
(Morales R. et al., 2007).Some are ME7, 22L, 139A, 139H, 263K, RML, 22C, 87A, 87V,
79A, 79V, 301C, 301V (L.J.M. van Keulen et al., 2015). Each scrapie strain
exhibits tropism targeting specific brain regions. 22L targets the cerebellum,
139A, the cerebral cortex and ME7, hippocampus.

scrapie strain was originally isolated from a scrapie infected sheep in the Suffolk flock of Moredun
Research Institute in the UK
(Zlotnik I and Rennie JC.,1963).The primary feature of ME7 strain is marked
neuronal loss in the CA1 Field of the hippocampus. ME7 infected animals have
been found to show marked vacuolation of the hippocampal, septal and thalamic
neutrophil. Hippocampal CA1 pyramidal neuron loss was discovered to be relatively
significant in ME7 (C. Cunningham et al., 2005). Mouse adapted ME7
predominantly target the polymorph layer of the dentate gyrus and stratum
lucidum, the CA3 field and the pyramidal layer with granular labeling and small
aggregates. It displayed a pattern of predominantly widespread granular
deposition within the neuropil and the presence of small aggregates (Beck et
al., 2012). In ME7 model of prion disease, proteinase K resistant PrPSc is readily detected at late stage of the
disease and is widespread throughout the hippocampus. Also, at the advanced
stage of the disease, there is a clear reduction in the volume of hippocampal
formation, hippocampal cell loss indicated by thinning of the stratum pyramidal
of CA1 and a decrease in the intensity and disorganization of staining of
several synaptic markers, including the synaptic vesicle protein
Synaptophysin.  (Ayodeji A. Asuni et
al.,2014). Also peculiar to ME7 infection is the observation that
behavioral changes and hippocampal synaptic loss occurs several weeks prior to
neuronal cell death (C. Cunningham et al., 2003).

Mouse adapted ME7 scrapie strain serially passaged in C57BL/6
induces neurodegeneration and gliogenesis in the hippocampus brain region of
the infected animals. The re-transmissibility of mouse adapted strain to
transgenic mice expressing ovine prion protein remains unknown. Hence in this study
the re-transmissibility and the distinct disease phenotype generated due to interspecies
transmission of mouse adapted ME7 scrapie strain to Ovine prion protein transgenic
mice was investigated.




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