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Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle.
[epidermolysis bullosa simplex]
The
ubiquitously
expressed
multifunctional
cytolinker
protein
plectin
is
essential
for
muscle
fiber
integrity
and
myofiber
cytoarchitecture
.
Patients
suffering
from
plectinopathy-associated
epidermolysis
bullosa
simplex
with
muscular
dystrophy
(
EBS-
MD
)
and
mice
lacking
plectin
in
skeletal
muscle
display
pathological
desmin
-
positive
protein
aggregation
and
misalignment
of
Z-
disks
,
which
are
hallmarks
of
myofibrillar
myopathies
(
MFMs
)
.
Here
,
we
developed
immortalized
murine
myoblast
cell
lines
to
examine
the
pathogenesis
of
plectinopathies
at
the
molecular
and
single
cell
level
.
Plectin-
deficient
myotubes
,
derived
from
myoblasts
,
were
fully
functional
and
mirrored
the
pathological
features
of
EBS-
MD
myofibers
,
including
the
presence
of
desmin
-
positive
protein
aggregates
and
a
concurrent
disarrangement
of
the
myofibrillar
apparatus
.
Using
this
cell
model
,
we
demonstrated
that
plectin
deficiency
leads
to
increased
intermediate
filament
network
and
sarcomere
dynamics
,
marked
upregulation
of
HSPs
,
and
reduced
myotube
resilience
following
mechanical
stretch
.
Currently
,
no
specific
therapy
or
treatment
is
available
to
improve
plectin
-related
or
other
forms
of
MFMs
;
therefore
,
we
assessed
the
therapeutic
potential
of
chemical
chaperones
to
relieve
plectinopathies
.
Treatment
with
4
-
phenylbutyrate
resulted
in
remarkable
amelioration
of
the
pathological
phenotypes
in
plectin
-
deficient
myotubes
as
well
as
in
plectin
-
deficient
mice
.
Together
,
these
data
demonstrate
the
biological
relevance
of
the
MFM
cell
model
and
suggest
that
this
model
has
potential
use
for
the
development
of
therapeutic
approaches
for
EBS-
MD
.
Diseases
Validation
Diseases presenting
"specific therapy"
symptom
carcinoma of the gallbladder
epidermolysis bullosa simplex
fabry disease
neonatal adrenoleukodystrophy
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