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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
.
