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Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits.
[cadasil]
Cerebral
autosomal
dominant
arteriopathy
with
subcortical
infarcts
and
leukoencephalopathy
(
CADASIL
)
represents
the
most
common
hereditary
form
of
cerebral
small
vessel
disease
characterized
by
early
-onset
stroke
and
premature
dementia
.
It
is
caused
by
mutations
in
the
transmembrane
receptor
Notch
3
,
which
promote
the
aggregation
and
accumulation
of
the
Notch
3
extracellular
domain
(
Notch
3
-
ECD
)
within
blood
vessel
walls
.
This
process
is
believed
to
mediate
the
abnormal
recruitment
and
dysregulation
of
additional
factors
including
extracellular
matrix
(
ECM
)
proteins
resulting
in
brain
vessel
dysfunction
.
Based
on
recent
evidence
indicating
a
role
for
the
transforming
growth
factor
-β
(
TGF-β
)
pathway
in
sporadic
and
familial
small
vessel
disease
we
studied
fibronectin
,
fibrillin-
1
and
latent
TGF-
β
binding
protein
1
(
LTBP-
1
)
,
three
ECM
constituents
involved
in
the
regulation
of
TGF-β
bioavailability
,
in
post-mortem
brain
tissue
from
CADASIL
patients
and
control
subjects
.
Fibronectin
and
fibrillin-
1
were
found
to
be
enriched
in
CADASIL
vessels
without
co
-localizing
with
Notch
3
-
ECD
deposits
,
likely
as
a
result
of
fibrotic
processes
secondary
to
aggregate
formation
.
In
contrast
,
LTBP-
1
showed
both
an
accumulation
and
a
striking
co
-localization
with
Notch
3
-
ECD
deposits
suggesting
specific
recruitment
into
aggregates
.
We
also
detected
increased
levels
of
the
TGF-β
prodomain
(
also
known
as
latency-associated
peptide
,
LAP
)
indicating
dysregulation
of
the
TGF-β
pathway
in
CADASIL
development
.
In
vitro
analyses
revealed
a
direct
interaction
between
LTBP-
1
and
Notch
3
-
ECD
and
demonstrated
a
specific
co
-aggregation
of
LTBP-
1
with
mutant
Notch
3
.
We
propose
LTBP-
1
as
a
novel
component
of
Notch
3
-
ECD
deposits
and
suggest
its
involvement
in
pathological
processes
triggered
by
Notch
3
-
ECD
aggregation
.