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Latent NOTCH3 epitopes unmasked in CADASIL and regulated by protein redox state.
[cadasil]
Cerebral
autosomal
dominant
arteriopathy
with
subcortical
infarcts
and
leukoencephalopathy
CADASIL
is
caused
by
more
than
a
hundred
NOTCH
3
mutations
.
Virtually
all
encoded
mutant
proteins
contain
an
odd
number
of
cysteines
.
As
such
,
structural
changes
in
NOTCH
3
may
be
the
primary
molecular
abnormality
in
CADASIL
.
Thus
,
we
sought
evidence
for
structurally
altered
NOTCH
3
protein
in
CADASIL
tissue
.
Four
antibodies
were
raised
in
rabbits
against
two
non-overlapping
N-
terminal
NOTCH
3
sequences
.
These
reagents
were
used
in
immunohistochemical
experiments
to
detect
epitopes
in
post-mortem
CADASIL
brains
(
n
=
8
)
,
control
brains
,
and
cells
overexpressing
NOTCH
3
.
To
determine
the
biochemical
nature
of
NOTCH
3
epitopes
,
we
used
these
antibodies
to
probe
pure
NOTCH
3
-
Fc
fusion
proteins
treated
with
acid
,
urea
,
guanidinium
,
ionic
detergents
,
acrylamide
,
and
thiol-
and
phosphorus-based
reductants
.
All
antibodies
avidly
stained
arteries
in
8
of
8
CADASIL
brain
samples
.
The
most
prominent
staining
was
in
degenerating
media
of
leptomeningeal
arteries
and
sclerotic
penetrating
vessels
.
Normal
appearing
vessels
from
control
brains
were
not
reactive
.
Antibodies
did
not
react
with
cultured
cells
overexpressing
NOTCH
3
or
with
purified
NOTCH
3
-
Fc
protein
.
Furthermore
,
treatment
of
pure
protein
with
acid
,
chaotropic
denaturants
,
alkylators
,
and
detergents
failed
to
unmask
N-
terminal
NOTCH
3
epitopes
.
Antibodies
,
however
,
recognized
novel
N-
terminal
epitopes
in
purified
NOTCH
3
-
Fc
protein
treated
with
three
different
reductants
(
DTT
,
beta
-mercaptoethanol
,
and
TCEP
)
.
We
conclude
that
CADASIL
arteries
feature
latent
N-
terminal
NOTCH
3
epitopes
,
suggesting
the
first
evidence
in
vivo
of
NOTCH
3
structural
alterations
.
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"first evidence in vivo"
symptom
cadasil
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