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Abcd2 is a strong modifier of the metabolic impairments in peritoneal macrophages of ABCD1-deficient mice.
[x-linked adrenoleukodystrophy]
The
inherited
peroxisomal
disorder
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
,
associated
with
neurodegeneration
and
inflammatory
cerebral
demyelination
,
is
caused
by
mutations
in
the
ABCD
1
gene
encoding
the
peroxisomal
ATP-binding
cassette
(
ABC
)
transporter
ABCD
1
(
ALDP
)
.
ABCD
1
transports
CoA-esters
of
very
long
-chain
fatty
acids
(
VLCFA
)
into
peroxisomes
for
degradation
by
β-oxidation
;
thus
,
ABCD
1
deficiency
results
in
VLCFA
accumulation
.
The
closest
homologue
,
ABCD
2
(
ALDRP
)
,
when
overexpressed
,
compensates
for
ABCD
1
deficiency
in
X-
ALD
fibroblasts
and
in
Abcd
1
-
deficient
mice
.
Microglia
/
macrophages
have
emerged
as
important
players
in
the
progression
of
neuroinflammation
.
Human
monocytes
,
lacking
significant
expression
of
ABCD
2
,
display
severely
impaired
VLCFA
metabolism
in
X-
ALD
.
Here
,
we
used
thioglycollate-elicited
primary
mouse
peritoneal
macrophages
(
MPMΦ
)
from
Abcd
1
and
Abcd
2
single
-
and
double
-
deficient
mice
to
establish
how
these
mutations
affect
VLCFA
metabolism
.
By
quantitative
RT-PCR
,
Abcd
2
mRNA
was
about
half
as
abundant
as
Abcd
1
mRNA
in
wild-
type
and
similarly
abundant
in
Abcd
1
-
deficient
MPMΦ
.
VLCFA
(
C
2
6
∶
0
)
accumulated
about
twofold
in
Abcd
1
-
deficient
MPMΦ
compared
with
wild-
type
controls
,
as
measured
by
gas
chromatography-mass
spectrometry
.
In
Abcd
2
-
deficient
macrophages
VLCFA
levels
were
normal
.
However
,
upon
Abcd
1
/
Abcd
2
double
-
deficiency
,
VLCFA
accumulation
was
markedly
increased
(
sixfold
)
compared
with
Abcd
1
-
deficient
MPMΦ
.
Elovl
1
mRNA
,
encoding
the
rate-limiting
enzyme
for
elongation
of
VLCFA
,
was
equally
abundant
across
all
genotypes
.
Peroxisomal
β-oxidation
of
C
2
6
∶
0
amounted
to
62
%
of
wild-
type
activity
in
Abcd
1
-
deficient
MPMΦ
and
was
significantly
more
impaired
(
29
%
residual
activity
)
upon
Abcd
1
/
Abcd
2
double
-
deficiency
.
Single
Abcd
2
deficiency
did
not
significantly
compromise
β-oxidation
of
C
2
6
∶
0
.
Thus
,
the
striking
accumulation
of
VLCFA
in
double
-
deficient
MPMΦ
compared
with
single
Abcd
1
deficiency
was
due
to
the
loss
of
ABCD
2
-
mediated
,
compensatory
transport
of
VLCFA
into
peroxisomes
.
We
propose
that
moderate
endogenous
expression
of
Abcd
2
in
Abcd
1
-
deficient
murine
macrophages
prevents
the
severe
metabolic
phenotype
observed
in
human
X-
ALD
monocytes
,
which
lack
appreciable
expression
of
ABCD
2
.
This
supports
upregulation
of
ABCD
2
as
a
therapeutic
concept
in
X-
ALD
.
Diseases
Validation
Diseases presenting
"abcd1 deficiency"
symptom
x-linked adrenoleukodystrophy
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