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Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL.
[cadasil]
Cerebral
autosomal
dominant
arteriopathy
with
subcortical
infarcts
and
leukoencephalopathy
,
or
CADASIL
,
one
of
the
most
common
inherited
small
vessel
diseases
of
the
brain
,
is
characterized
by
a
progressive
loss
of
vascular
smooth
muscle
cells
and
extracellular
matrix
accumulation
.
The
disease
is
caused
by
highly
stereotyped
mutations
within
the
extracellular
domain
of
the
NOTCH
3
receptor
(
Notch
3
(
ECD
)
)
that
result
in
an
odd
number
of
cysteine
residues
.
While
CADASIL
-associated
NOTCH
3
mutations
differentially
affect
NOTCH
3
receptor
function
and
activity
,
they
all
are
associated
with
early
accumulation
of
Notch
3
(
ECD
)
-
containing
aggregates
in
small
vessels
.
We
still
lack
mechanistic
explanation
to
link
NOTCH
3
mutations
with
small
vessel
pathology
.
Herein
,
we
hypothesized
that
excess
Notch
3
(
ECD
)
could
recruit
and
sequester
functionally
important
proteins
within
small
vessels
of
the
brain
.
We
performed
biochemical
,
nano
-liquid
chromatography-tandem
mass
spectrometry
and
immunohistochemical
analyses
,
using
cerebral
and
arterial
tissue
derived
from
patients
with
CADASIL
and
mouse
models
of
CADASIL
that
exhibit
vascular
lesions
in
the
end-
and
early
-
stage
of
the
disease
,
respectively
.
Biochemical
fractionation
of
brain
and
artery
samples
demonstrated
that
mutant
Notch
3
(
ECD
)
accumulates
in
disulphide
cross-linked
detergent-insoluble
aggregates
in
mice
and
patients
with
CADASIL
.
Further
proteomic
and
immunohistochemical
analyses
identified
two
functionally
important
extracellular
matrix
proteins
,
tissue
inhibitor
of
metalloproteinases
3
(
TIMP
3
)
and
vitronectin
(
VTN
)
that
are
sequestered
into
Notch
3
(
ECD
)
-
containing
aggregates
.
Using
cultured
cells
,
we
show
that
increased
levels
or
aggregation
of
Notch
3
enhances
the
formation
of
Notch
3
(
ECD
)
-
TIMP
3
complex
,
promoting
TIMP
3
recruitment
and
accumulation
.
In
turn
,
TIMP
3
promotes
complex
formation
including
NOTCH
3
and
VTN
.
In
vivo
,
brain
vessels
from
mice
and
patients
with
CADASIL
exhibit
elevated
levels
of
both
insoluble
cross-linked
and
soluble
TIMP
3
species
.
Moreover
,
reverse
zymography
assays
show
a
significant
elevation
of
TIMP
3
activity
in
the
brain
vessels
from
mice
and
patients
with
CADASIL
.
Collectively
,
our
findings
lend
support
to
a
Notch
3
(
ECD
)
cascade
hypothesis
in
CADASIL
disease
pathology
,
which
posits
that
aggregation
/
accumulation
of
Notch
3
(
ECD
)
in
the
brain
vessels
is
a
central
event
,
promoting
the
abnormal
recruitment
of
functionally
important
extracellular
matrix
proteins
that
may
ultimately
cause
multifactorial
toxicity
.
Specifically
,
our
results
suggest
a
dysregulation
of
TIMP
3
activity
,
which
could
contribute
to
mutant
Notch
3
(
ECD
)
toxicity
by
impairing
extracellular
matrix
homeostasis
in
small
vessels
.
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