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Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy.
[adrenomyeloneuropathy]
X-
linked
adrenoleukodystrophy
is
a
neurometabolic
disorder
caused
by
inactivation
of
the
peroxisomal
ABCD
1
transporter
of
very
long
-chain
fatty
acids
.
In
mice
,
ABCD
1
loss
causes
late
onset
axonal
degeneration
in
the
spinal
cord
in
association
with
locomotor
disability
resembling
the
most
common
phenotype
in
patients
,
adrenomyeloneuropathy
.
Increasing
evidence
indicates
that
oxidative
stress
and
bioenergetic
failure
play
major
roles
in
the
pathogenesis
of
X-
linked
adrenoleukodystrophy
.
In
this
study
,
we
aimed
to
evaluate
whether
mitochondrial
biogenesis
is
affected
in
X-
linked
adrenoleukodystrophy
.
We
demonstrated
that
Abcd
1
null
mice
show
reduced
mitochondrial
DNA
concomitant
with
downregulation
of
mitochondrial
biogenesis
pathway
driven
by
PGC
-
1
α
/
PPAR
γ
and
reduced
expression
of
mitochondrial
proteins
cytochrome
c
,
NDUFB
8
and
VDAC
.
Moreover
,
we
show
that
the
oral
administration
of
pioglitazone
,
an
agonist
of
PPAR
γ
,
restored
mitochondrial
content
and
expression
of
master
regulators
of
biogenesis
,
neutralized
oxidative
damage
to
proteins
and
DNA
,
and
reversed
bioenergetic
failure
in
terms
of
ATP
levels
,
NAD
+
/
NADH
ratios
,
pyruvate
kinase
and
glutathione
reductase
activities
.
Most
importantly
,
the
treatment
halted
locomotor
disability
and
axonal
damage
in
X-
linked
adrenoleukodystrophy
mice
.
These
results
lend
support
to
the
use
of
pioglitazone
in
clinical
trials
with
patients
with
adrenomyeloneuropathy
and
reveal
novel
molecular
mechanisms
of
action
of
pioglitazone
in
neurodegeneration
.
Future
studies
should
address
the
effects
of
this
anti-diabetic
drug
on
other
axonopathies
in
which
oxidative
stress
and
mitochondrial
dysfunction
are
contributing
factors
.
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