Proteolytic processing of the cellular prion protein ‐ its importance in health and as a modulator of TSE disease susceptibility in sheep
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Authors
Abstract
Expression
of
the
cellular
prion
protein
(PrPC)
from
the
PRNP
gene
is
crucial
for
the
development
of
a
group
of
fatal
neurodegenerative
disorders
called
prion
diseases.
During
prion
infection
a
misfolded
protein
homologue
of
PrPC,
PrPSc
causes
further
misfolding
on
interaction
with
native
PrPC
molecules.
PrPSc
is
highly
resistant
to
proteinase
K
and
aggregation
of
this
protein
is
considered
a
hallmark
of
infection.
Sheep
are
considered
a
model
of
natural
infection
and
susceptibility
to
scrapie
in
sheep
is
defined
by
polymorphisms
in
the
PRNP
gene.
It
is
still
not
fully
understood
how
these
polymorphisms
regulate
the
conversion
process
or
which
other
co-‐factors
are
involved.
One
such
factor
may
be
the
truncation
of
PrPC
via
proteolytic
processing
in
the
form
of
two
main
cleavage
events,
known
as
α-‐
and
β-‐cleavage.
In
sheep
α-‐cleavage
cuts
at
amino
acid
115,
creating
two
truncated
proteins
C1
and
N1
and
represents
the
main
cleavage
event
in
healthy
brain.
β-‐Cleavage
creates
a
longer
C-‐terminal
fragment,
C2
and
corresponding
N-‐terminal
fragment
N2,
cutting
around
amino
acid
92
in
sheep.
Truncated
forms
of
PrPC
have
been
shown
to
represent
around
50
%
of
total
residual
PrP
in
brain
and
may
be
an
important
determinant
of
disease
through
both
decreasing
the
amount
of
full
length
PrPC
available
for
conversion
and
through
functions
associated
with
the
truncated
fragments.
The
research
presented
has
shown
that
increased
production
of
an
α-‐cleavage
fragment
C1
in
brain
is
associated
with
TSE
resistant
genotype
ARR/ARR,
while
the
presence
of
C2
fragment
is
affiliated
with
scrapie
susceptible
PRNP
genotypes
in
brain.
There
was
no
difference
in
the
levels
of
full
length
PrPC
in
these
genotypes
suggesting
that
PrP
expression
does
not
directly
correlate
to
susceptibility
in
this
model.
To
assess
if
PrPC
fragments
could
affect
the
conversion
during
disease
in-‐vitro
fibrillisation
assays
were
performed
using
novel truncated
recombinant
proteins.
These
truncated
proteins,
although
not
thought
to
convert
to
PK
resistant
PrPSc
during
disease,
can
form
amyloid
fibrils.
However,
these
fibrils
appear
to
be
less
neurotoxic
when
compared
to
fibrils
produced
by
full
length
PrPC.
Only
the
truncated
fragments
derived
from
the
ARR
allele
inhibit
in-‐vitro
fibrillisation
of
other
allelic
PrPC
variants.
Furthermore,
treatment
of
infected
cells
in
culture
with
recombinant
C1ARR
led
to
a
decrease
in
the
formation
of
disease
associated
PrPSc.
In
conclusion,
genetic
variations
in
levels
of
PrP
truncated
fragments
may
add
to
the
complexity
of
genetic
determinants
of
prion
disease.
In
parallel
with
polymorphism-‐dependant
conversion
abilities,
varying
α-‐cleavage
of
ovine
PrPC
may
help
to
explain
genetic
resistance
in
sheep.
The
inhibitory
effects
of
C1,
illustrated
in-‐
vitro
may
represent
a
therapeutic
avenue
in
the
treatment
of
prion
disease.
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