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PEX13 deficiency in mouse brain as a model of Zellweger syndrome: abnormal cerebellum formation, reactive gliosis and oxidative stress.
[zellweger syndrome]
Delayed
cerebellar
development
is
a
hallmark
of
Zellweger
syndrome
(
ZS
)
,
a
severe
neonatal
neurodegenerative
disorder
.
ZS
is
caused
by
mutations
in
PEX
genes
,
such
as
PEX
13
,
which
encodes
a
protein
required
for
import
of
proteins
into
the
peroxisome
.
The
molecular
basis
of
ZS
pathogenesis
is
not
known
.
We
have
created
a
conditional
mouse
mutant
with
brain
-
restricted
deficiency
of
PEX
13
that
exhibits
cerebellar
morphological
defects
.
PEX
13
brain
mutants
survive
into
the
postnatal
period
,
with
the
majority
dying
by
35
days
,
and
with
survival
inversely
related
to
litter
size
and
weaning
body
weight
.
The
impact
on
peroxisomal
metabolism
in
the
mutant
brain
is
mixed
:
plasmalogen
content
is
reduced
,
but
very
-
long
-chain
fatty
acids
are
normal
.
PEX
13
brain
mutants
exhibit
defects
in
reflex
and
motor
development
that
correlate
with
impaired
cerebellar
fissure
and
cortical
layer
formation
,
granule
cell
migration
and
Purkinje
cell
layer
development
.
Astrogliosis
and
microgliosis
are
prominent
features
of
the
mutant
cerebellum
.
At
the
molecular
level
,
cultured
cerebellar
neurons
from
E
19
PEX
13
-
null
mice
exhibit
elevated
levels
of
reactive
oxygen
species
and
mitochondrial
superoxide
dismutase-
2
(
MnSOD
)
,
and
show
enhanced
apoptosis
together
with
mitochondrial
dysfunction
.
PEX
13
brain
mutants
show
increased
levels
of
MnSOD
in
cerebellum
.
Our
findings
suggest
that
PEX
13
deficiency
leads
to
mitochondria-mediated
oxidative
stress
,
neuronal
cell
death
and
impairment
of
cerebellar
development
.
Thus
,
PEX
13
-
deficient
mice
provide
a
valuable
animal
model
for
investigating
the
molecular
basis
and
treatment
of
ZS
cerebellar
pathology
.
Diseases
Validation
Diseases presenting
"cortical layer formation"
symptom
zellweger syndrome
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