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Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients.
[adrenomyeloneuropathy]
Because
of
a
lack
of
an
appropriate
animal
model
system
and
the
inaccessibility
of
human
oligodendrocytes
in
vivo
,
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
-
induced
pluripotent
stem
cells
(
iPSCs
)
would
provide
a
unique
cellular
model
for
studying
etiopathophysiology
and
development
of
therapeutics
for
X-
ALD
.
We
generated
and
characterized
iPSCs
of
the
2
major
types
of
X-
ALD
,
childhood
cerebral
ALD
(
CCALD
)
and
adrenomyeloneuropathy
(
AMN
)
,
and
differentiated
them
into
oligodendrocytes
and
neurons
.
We
evaluated
disease-relevant
phenotypes
by
pharmacological
and
genetic
approaches
.
We
established
iPSCs
from
the
patients
with
CCALD
and
AMN
.
Both
CCALD
and
AMN
iPSCs
normally
differentiated
into
oligodendrocytes
,
the
cell
type
primarily
affected
in
the
X-
ALD
brain
,
indicating
no
developmental
defect
due
to
the
ABCD
1
mutations
.
Although
low
in
X-
ALD
iPSCs
,
very
long
chain
fatty
acid
(
VLCFA
)
level
was
significantly
increased
after
oligodendrocyte
differentiation
.
VLCFA
accumulation
was
much
higher
in
CCALD
oligodendrocytes
than
AMN
oligodendrocytes
but
was
not
significantly
different
between
CCALD
and
AMN
neurons
,
indicating
that
the
severe
clinical
manifestations
in
CCALD
might
be
associated
with
abnormal
VLCFA
accumulation
in
oligodendrocytes
.
Furthermore
,
the
abnormal
accumulation
of
VLCFA
in
the
X-
ALD
oligodendrocytes
can
be
reduced
by
the
upregulated
ABCD
2
gene
expression
after
treatment
with
lovastatin
or
4
-
phenylbutyrate
.
X-
ALD
iPSC
model
recapitulates
the
key
events
of
disease
development
(
ie
,
VLCFA
accumulation
in
oligodendrocytes
)
,
provides
new
clues
for
better
understanding
of
the
disease
,
and
allows
for
early
and
accurate
diagnosis
of
the
disease
subtypes
.
X-
ALD
oligodendrocytes
can
be
a
useful
cell
model
system
to
develop
new
therapeutics
for
treating
X-
ALD
.
Diseases
Validation
Diseases presenting
"induced pluripotent stem cells (ipscs"
symptom
adrenomyeloneuropathy
dystrophic epidermolysis bullosa
severe combined immunodeficiency
werner syndrome
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