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Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease.
[canavan disease]
Genetic
mutations
that
severely
diminish
the
activity
of
aspartoacylase
(
ASPA
)
result
in
the
fatal
brain
dysmyelinating
disorder
,
Canavan
disease
.
There
is
no
effective
treatment
.
ASPA
produces
free
acetate
from
the
concentrated
brain
metabolite
,
N-
acetylaspartate
(
NAA
)
.
Because
acetyl
coenzyme
A
is
a
key
building
block
for
lipid
synthesis
,
we
postulated
that
the
inability
to
catabolize
NAA
leads
to
a
brain
acetate
deficiency
during
a
critical
period
of
CNS
development
,
impairing
myelination
and
possibly
other
aspects
of
brain
development
.
We
tested
the
hypothesis
that
acetate
supplementation
during
postnatal
myelination
would
ameliorate
the
severe
phenotype
associated
with
ASPA
deficiency
using
the
tremor
rat
model
of
Canavan
disease
.
Glyceryltriacetate
(
GTA
)
was
administered
orally
to
tremor
rats
starting
7
days
after
birth
,
and
was
continued
in
food
and
water
after
weaning
.
Motor
function
,
myelin
lipids
,
and
brain
vacuolation
were
analyzed
in
GTA-treated
and
untreated
tremor
rats
.
Significant
improvements
were
observed
in
motor
performance
and
myelin
galactocerebroside
content
in
tremor
rats
treated
with
GTA
.
Further
,
brain
vacuolation
was
modestly
reduced
,
and
these
reductions
were
positively
correlated
with
improved
motor
performance
.
We
also
examined
the
expression
of
the
acetyl
coenzyme
A
synthesizing
enzyme
acetyl
coenzyme
A
synthase
1
and
found
upregulation
of
expression
in
tremor
rats
,
with
a
return
to
near
normal
expression
levels
in
GTA-treated
tremor
rats
.
These
results
confirm
the
critical
role
played
by
NAA-derived
acetate
in
brain
myelination
and
development
,
and
demonstrate
the
potential
usefulness
of
acetate
therapy
for
the
treatment
of
Canavan
disease
.
Diseases
Validation
Diseases presenting
"myelin galactocerebroside content in tremor rats treated with gta"
symptom
canavan disease
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