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Pharmacological chaperones increase residual β-galactocerebrosidase activity in fibroblasts from Krabbe patients.
[krabbe disease]
Krabbe
disease
or
globoid
cell
leukodystrophy
is
a
degenerative
,
lysosomal
storage
disease
resulting
from
the
deficiency
of
β-galactocerebrosidase
activity
.
This
enzyme
catalyzes
the
lysosomal
hydrolysis
of
galactocerebroside
and
psychosine
.
Krabbe
disease
is
inherited
as
an
autosomal
recessive
trait
,
and
many
of
the
70
disease-causing
mutations
identified
in
the
GALC
gene
are
associated
with
protein
misfolding
.
Recent
studies
have
shown
that
enzyme
inhibitors
can
sometimes
translocate
misfolded
polypeptides
to
their
appropriate
target
organelle
bypassing
the
normal
cellular
quality
control
machinery
and
resulting
in
enhanced
activity
.
In
search
for
pharmacological
chaperones
that
could
rescue
the
β-galactocerebrosidase
activity
,
we
investigated
the
effect
of
α-
Lobeline
or
3
'
,
4
'
,
7
-
trihydroxyisoflavone
on
several
patient-derived
fibroblast
cell
lines
carrying
missense
mutations
,
rather
than
on
transduced
cell
lines
.
Incubation
of
these
cell
lines
with
α-lobeline
or
3
'
,
4
'
,
7
-
trihydroxyisoflavone
leads
to
an
increase
of
β-galacocerebrosidase
activity
in
p
.
G
553
R
+
p
.
G
553
R
,
in
p
.
E
130
K
+
p
.
N
295
T
and
in
p
.
G
57
S
+
p
.
G
57
S
mutant
forms
over
the
critical
threshold
.
The
low
but
sustained
expression
of
β-galactocerebrosidase
induced
by
these
compounds
is
a
promising
result
;
in
fact
,
it
is
known
that
residual
enzyme
activity
of
only
15
-
20
%
is
sufficient
for
clinical
efficacy
.
The
molecular
interaction
of
the
two
chaperones
with
β-galactocerebrosidase
is
also
supported
by
in
silico
analysis
.
Collectively
,
our
combined
in
silico-
in
vitro
approach
indicate
α-lobeline
and
3
'
,
4
'
,
7
-
trihydroxyisoflavone
as
two
potential
pharmacological
chaperones
for
the
treatment
or
improvement
of
quality
of
life
in
selected
Krabbe
disease
patients
.
Diseases
Validation
Diseases presenting
"leukodystrophy"
symptom
achondroplasia
adrenomyeloneuropathy
alexander disease
cadasil
canavan disease
carcinoma of the gallbladder
classical phenylketonuria
coats disease
fabry disease
gm1 gangliosidosis
krabbe disease
neonatal adrenoleukodystrophy
phenylketonuria
pyruvate dehydrogenase deficiency
wiskott-aldrich syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
This symptom has already been validated