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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
"the deficiency of β-galactocerebrosidase activity"
symptom
krabbe disease
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