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Characterization and application of a disease-cell model for a neurodegenerative lysosomal disease.
[krabbe disease]
Disease-cell
models
that
recapitulate
specific
molecular
phenotypes
are
essential
for
the
investigation
of
molecular
pathogenesis
of
neurodegenerative
diseases
including
lysosomal
storage
diseases
(
LSDs
)
with
predominant
neurological
manifestations
.
Herein
we
report
the
development
and
characterization
of
a
cell
model
for
a
rapid
neurodegenerative
LSDs
,
globoid-cell
leukodystrophy
(
GLD
)
,
mostly
known
as
Krabbe
disease
.
GLD
is
caused
by
the
deficiency
of
β-galactocerebrosidase
(
GALC
)
,
a
lysosomal
enzyme
that
hydrolyzes
two
glycosphingolipids
,
psychosine
and
galactosylceramide
.
Unfortunately
,
the
available
culture
fibroblasts
from
GLD
patients
consist
of
a
limited
research
tool
as
these
cells
fail
to
accumulate
psychosine
,
the
central
pathogenic
glycosphingolipid
in
this
LSD
that
results
in
severe
demyelination
.
Firstly
,
we
obtained
brain
samples
from
the
Twitcher
(
Twi
)
mice
(
GALC
(
twi
/
twi
)
)
,
the
natural
mouse
model
with
GALC
deficiency
.
We
immortalized
the
primary
neuroglial
cultured
cells
with
SV
40
large
T
antigen
,
generating
the
145
M-Twi
and
the
145
C-Wt
cell
lines
from
the
Twi
and
control
mice
,
respectively
.
Both
cell
lines
expressed
specific
oligodendrocyte
markers
including
A
2
B
5
and
GalC
.
The
145
M-Twi
cells
showed
biochemical
and
cellular
disturbances
related
to
GLD
neuropathogenesis
including
remarkable
caspase-
3
activation
,
release
of
cytochrome
C
into
the
cytosol
and
expansion
of
the
lysosomal
compartment
.
Under
treatment
with
glycosphingolipids
,
145
M-Twi
cells
showed
increased
LC
3
B
levels
,
a
marker
of
autophagy
.
Using
the
LC
-
MS
/
MS
method
that
we
developed
,
the
145
M-Twi
cells
showed
significantly
higher
levels
of
psychosine
.
The
145
M-Twi
and
145
C-Wt
lines
allowed
the
development
of
a
robust
throughput
LC
-
MS
/
MS
assay
to
measure
cellular
psychosine
levels
.
In
this
throughput
assay
,
l-cycloserine
showed
to
significantly
reduce
the
145
M-Twi
cellular
levels
of
psychosine
.
The
established
145
M-Twi
cells
are
powerful
research
tools
to
investigate
the
neurologically
relevant
pathogenic
pathways
as
well
as
to
develop
primary
screening
assays
for
the
identification
of
therapeutic
agents
for
GLD
and
potentially
other
glycosphingolipid
disorders
.
Diseases
Validation
Diseases presenting
"severe demyelination"
symptom
krabbe disease
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