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Aberrant production of tenascin-C in globoid cell leukodystrophy alters psychosine-induced microglial functions.
[krabbe disease]
Globoid
cell
leukodystrophy
(
GLD
)
,
or
Krabbe
disease
,
is
a
rare
and
often
fatal
demyelinating
disease
caused
by
mutations
in
the
galactocerebrosidase
(
galc
)
gene
that
result
in
accumulation
of
galactosylsphingosine
(
psychosine
)
.
We
recently
reported
that
the
extracellular
matrix
(
ECM
)
protease
,
matrix
metalloproteinase-
3
,
is
elevated
in
GLD
and
that
it
regulates
psychosine-induced
microglial
activation
.
Here
,
we
examined
central
nervous
system
ECM
component
expression
in
human
GLD
patients
and
in
the
twitcher
mouse
model
of
GLD
using
immunohistochemistry
.
The
influence
of
ECM
proteins
on
primary
murine
microglial
responses
to
psychosine
was
evaluated
using
ECM
proteins
as
substrates
and
analyzed
by
quantitative
real-time
polymerase
chain
reaction
,
immunocytochemistry
,
and
ELISA
.
Functional
analysis
of
microglial
cytotoxicity
was
performed
on
oligodendrocytes
in
coculture
,
and
cell
death
was
measured
by
lactose
dehydrogenase
assay
.
Tenascin-
C
(
TnC
)
was
expressed
at
higher
levels
in
human
GLD
and
in
twitcher
mice
versus
controls
.
Microglial
responses
to
psychosine
were
enhanced
by
TnC
,
as
determined
by
an
increase
in
globoid-like
cell
formation
,
matrix
metalloproteinase-
3
mRNA
expression
,
and
higher
toxicity
toward
oligodendrocytes
in
culture
.
These
findings
were
consistent
with
a
shift
toward
the
M
1
microglial
phenotype
in
TnC-grown
microglia
.
Thus
,
elevated
TnC
expression
in
GLD
modified
microglial
responses
to
psychosine
.
These
data
offer
a
novel
perspective
and
enhance
understanding
of
the
microglial
contribution
to
GLD
pathogenesis
.
Diseases
Validation
Diseases presenting
"immunocytochemistry"
symptom
krabbe disease
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