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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
"positive cells"
symptom
canavan disease
carcinoma of the gallbladder
coats disease
congenital diaphragmatic hernia
dedifferentiated liposarcoma
epidermolysis bullosa simplex
erythropoietic protoporphyria
esophageal adenocarcinoma
hodgkin lymphoma, classical
severe combined immunodeficiency
werner syndrome
x-linked adrenoleukodystrophy
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