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Aspartoacylase-lacZ knockin mice: an engineered model of Canavan disease.
[canavan disease]
Canavan
Disease
(
CD
)
is
a
recessive
leukodystrophy
caused
by
loss
of
function
mutations
in
the
gene
encoding
aspartoacylase
(
ASPA
)
,
an
oligodendrocyte-enriched
enzyme
that
hydrolyses
N-
acetylaspartate
(
NAA
)
to
acetate
and
aspartate
.
The
neurological
phenotypes
of
different
rodent
models
of
CD
vary
considerably
.
Here
we
report
on
a
novel
targeted
aspa
mouse
mutant
expressing
the
bacterial
β-
Galactosidase
(
lacZ
)
gene
under
the
control
of
the
aspa
regulatory
elements
.
X-Gal
staining
in
known
ASPA
expression
domains
confirms
the
integrity
of
the
modified
locus
in
heterozygous
aspa
lacZ-knockin
(
aspa
(
lacZ
/
+
)
)
mice
.
In
addition
,
abundant
ASPA
expression
was
detected
in
Schwann
cells
.
Homozygous
(
aspa
(
lacZ
/
lacZ
)
)
mutants
are
ASPA
-
deficient
,
show
CD-like
histopathology
and
moderate
neurological
impairment
with
behavioural
deficits
that
are
more
pronounced
in
aspa
(
lacZ
/
lacZ
)
males
than
females
.
Non-invasive
ultrahigh
field
proton
magnetic
resonance
spectroscopy
revealed
increased
levels
of
NAA
,
myo-inositol
and
taurine
in
the
aspa
(
lacZ
/
lacZ
)
brain
.
Spongy
degeneration
was
prominent
in
hippocampus
,
thalamus
,
brain
stem
,
and
cerebellum
,
whereas
white
matter
of
optic
nerve
and
corpus
callosum
was
spared
.
Intracellular
vacuolisation
in
astrocytes
coincides
with
axonal
swellings
in
cerebellum
and
brain
stem
of
aspa
(
lacZ
/
lacZ
)
mutants
indicating
that
astroglia
may
act
as
an
osmolyte
buffer
in
the
aspa-
deficient
CNS
.
In
summary
,
the
aspa
(
lacZ
)
mouse
is
an
accurate
model
of
CD
and
an
important
tool
to
identify
novel
aspects
of
its
complex
pathology
.
Diseases
Validation
Diseases presenting
"leukodystrophy"
symptom
achondroplasia
adrenomyeloneuropathy
alexander disease
cadasil
canavan disease
carcinoma of the gallbladder
classical phenylketonuria
coats disease
fabry disease
gm1 gangliosidosis
krabbe disease
neonatal adrenoleukodystrophy
phenylketonuria
pyruvate dehydrogenase deficiency
wiskott-aldrich syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
This symptom has already been validated