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Lack of aspartoacylase activity disrupts survival and differentiation of neural progenitors and oligodendrocytes in a mouse model of Canavan disease.
[canavan disease]
Loss
of
the
oligodendrocyte
(
OL
)
-
specific
enzyme
aspartoacylase
(
ASPA
)
from
gene
mutation
results
in
the
sponginess
and
loss
of
white
matter
(
WM
)
in
Canavan
disease
(
CD
)
.
This
study
addresses
the
fate
of
OLs
during
the
pathophysiology
of
CD
in
an
adult
ASPA
knockout
(
KO
)
mouse
strain
.
Massive
arrays
of
neural
stem
/
progenitor
cells
,
immunopositive
for
PSA-NCAM
,
nestin
,
vimentin
,
and
NG
2
,
were
observed
within
the
severely
affected
spongy
WM
of
the
KO
mouse
brain
.
In
these
mice
,
G
1
-
-
>
S
cell
cycle
progression
was
confirmed
by
an
increase
in
cdk
2
-
kinase
activity
,
a
reduction
in
mitotic
inhibitors
p
21
(
Cip
1
)
and
p
27
(
Kip
1
)
,
and
an
increase
in
bromodeoxyuridine
(
BrdU
)
incorporation
.
Highly
acetylated
nuclear
histones
H
2
B
and
H
3
were
detected
in
adult
KO
mouse
WM
,
suggesting
the
existence
of
noncompact
chromatin
as
seen
during
early
development
.
Costaining
for
BrdU-
or
Ki
67
-
positive
cells
with
markers
for
neural
progenitors
confirmed
a
continuous
generation
of
OL
lineage
cells
in
KO
WM
.
We
observed
a
severe
reduction
in
21
.
5
-
and
18
.
5
-
kDa
myelin
basic
protein
and
PLP
/
DM
20
proteolipid
proteins
combined
with
a
decrease
in
myelinated
fibers
and
a
perinuclear
retention
of
myelin
protein
staining
,
indicating
impairment
in
protein
trafficking
.
Death
of
OLs
,
neurons
,
and
astrocytes
was
identified
in
every
region
of
the
KO
brain
.
Immature
OLs
constituted
the
largest
population
of
dying
cells
,
particularly
in
WM
.
We
also
report
an
early
expression
of
full-length
ASPA
mRNA
in
normal
mouse
brain
at
embryonic
day
12
.
5
,
when
OL
progenitors
first
appear
during
development
.
These
findings
support
involvement
of
ASPA
in
CNS
development
and
function
.
Diseases
Validation
Diseases presenting
"loss of white matter"
symptom
canavan disease
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