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Impaired very long-chain acyl-CoA β-oxidation in human X-linked adrenoleukodystrophy fibroblasts is a direct consequence of ABCD1 transporter dysfunction.
[zellweger syndrome]
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
,
an
inherited
peroxisomal
disorder
,
is
caused
by
mutations
in
the
ABCD
1
gene
encoding
the
peroxisomal
ATP-binding
cassette
(
ABC
)
transporter
ABCD
1
(
adrenoleukodystrophy
protein
,
ALDP
)
.
Biochemically
,
X-
ALD
is
characterized
by
an
accumulation
of
very
long
-chain
fatty
acids
and
partially
impaired
peroxisomal
β-oxidation
.
In
this
study
,
we
used
primary
human
fibroblasts
from
X-
ALD
and
Zellweger
syndrome
patients
to
investigate
the
peroxisomal
β-oxidation
defect
.
Our
results
show
that
the
degradation
of
C
2
6
:
0
-
CoA
esters
is
as
severely
impaired
as
degradation
of
unesterified
very
long
-chain
fatty
acids
in
X-
ALD
and
is
abolished
in
Zellweger
syndrome
.
Interestingly
,
the
β-oxidation
rates
for
both
C
2
6
:
0
-
CoA
and
C
2
2
:
0
-
CoA
were
similarly
affected
,
although
C
2
2
:
0
does
not
accumulate
in
patient
fibroblasts
.
Furthermore
,
we
show
that
the
β-oxidation
defect
in
X-
ALD
is
directly
caused
by
ABCD
1
dysfunction
as
blocking
ABCD
1
function
with
a
specific
antibody
reduced
β-oxidation
to
levels
observed
in
X-
ALD
fibroblasts
.
By
quantification
of
mRNA
and
protein
levels
of
the
peroxisomal
ABC
transporters
and
by
blocking
with
specific
antibodies
,
we
found
that
residual
β-oxidation
activity
toward
C
2
6
:
0
-
CoA
in
X-
ALD
fibroblasts
is
mediated
by
ABCD
3
,
although
the
efficacy
of
ABCD
3
appeared
to
be
much
lower
than
that
of
ABCD
1
.
Finally
,
using
isolated
peroxisomes
,
we
show
that
β-oxidation
of
C
2
6
:
0
-
CoA
is
independent
of
additional
CoA
but
requires
a
cytosolic
factor
of
>
10
-
kDa
molecular
mass
that
is
resistant
to
N-
ethylmaleimide
and
heat
inactivation
.
In
conclusion
,
our
findings
in
human
cells
suggest
that
,
in
contrast
to
yeast
cells
,
very
long
-chain
acyl-
CoA
esters
are
transported
into
peroxisomes
by
ABCD
1
independently
of
additional
synthetase
activity
.
Diseases
Validation
Diseases presenting
"factor of >10"
symptom
x-linked adrenoleukodystrophy
zellweger syndrome
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