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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
"leukodystrophy"
symptom
achondroplasia
adrenomyeloneuropathy
alexander disease
cadasil
canavan disease
carcinoma of the gallbladder
classical phenylketonuria
coats disease
fabry disease
gm1 gangliosidosis
krabbe disease
neonatal adrenoleukodystrophy
phenylketonuria
pyruvate dehydrogenase deficiency
wiskott-aldrich syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
This symptom has already been validated