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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
"neurodegeneration"
symptom
adrenomyeloneuropathy
alexander disease
cadasil
canavan disease
classical phenylketonuria
fabry disease
gm1 gangliosidosis
hereditary cerebral hemorrhage with amyloidosis
krabbe disease
neonatal adrenoleukodystrophy
neuralgic amyotrophy
oculocutaneous albinism
pyruvate dehydrogenase deficiency
triple a syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
This symptom has already been validated