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Loss of AMP-activated protein kinase in X-linked adrenoleukodystrophy patient-derived fibroblasts and lymphocytes.
[adrenomyeloneuropathy]
X-Adrenoleukodystrophy
(
X-
ALD
)
is
a
peroxisomal
disorder
characterized
by
accumulation
of
very
-
long
-chain
(
VLC
)
fatty
acids
,
which
induces
inflammatory
disease
and
alterations
in
cellular
redox
,
both
of
which
are
reported
to
play
a
role
in
the
pathogenesis
of
the
severe
form
of
the
disease
(
childhood
cerebral
ALD
)
.
While
the
mutation
defect
in
ABCD
1
gene
is
common
to
all
forms
of
X-
ALD
it
fails
to
account
for
the
spectrum
of
phenotypic
variability
seen
in
X-
ALD
patients
,
strongly
suggesting
a
role
for
as
yet
unidentified
modifier
gene
(
s
)
.
Here
we
report
,
for
the
first
time
,
loss
of
AMP
-activated
protein
kinase
alpha
1
(
AMPKα
1
)
in
patient-derived
fibroblasts
and
lymphocytes
of
the
severe
cerebral
form
of
X-
ALD
(
ALD
)
,
and
not
in
the
milder
adrenomyeloneuropathy
(
AMN
)
form
.
Decrease
in
AMPK
was
observed
at
both
protein
and
mRNA
levels
.
AMPK
loss
in
ALD
patient-derived
fibroblasts
was
associated
with
increased
ubiquitination
.
Using
the
Seahorse
Bioscience
XF
(
e
)
96
Flux
Analyzer
for
measuring
the
mitochondrial
oxygen
consumption
and
extracellular
acidification
rate
we
show
that
ALD
patient-derived
fibroblasts
have
a
significantly
lower
"
metabolic
state
"
than
AMN
fibroblasts
.
Unstimulated
ALD
patient-derived
lymphocytes
had
significantly
higher
proinflammatory
gene
expression
.
Selective
AMPK
loss
represents
a
novel
physiopathogenic
factor
in
X-
ALD
disease
mechanism
.
Strategies
aimed
at
upregulating
/
recovering
AMPK
levels
might
have
beneficial
therapeutic
effects
in
X-
ALD
.
