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MMP-3 mediates psychosine-induced globoid cell formation: implications for leukodystrophy pathology.
[krabbe disease]
Globoid
cell
leukodystrophy
(
GLD
)
or
Krabbe
disease
,
is
a
fatal
demyelinating
disease
attributed
to
mutations
in
the
galactocerebrosidase
(
GALC
)
gene
.
Loss
of
function
mutations
in
GALC
result
in
accumulation
of
the
glycolipid
intermediate
,
galactosylsphingosine
(
psychosine
)
.
Due
to
the
cytotoxicity
of
psychosine
,
it
has
been
hypothesized
that
accumulated
psychosine
underlie
the
pathophysiology
of
GLD
.
However
,
the
cellular
mechanisms
of
GLD
pathophysiology
remain
unclear
.
Globoid
cells
,
multinucleated
microglia
/
macrophages
in
the
central
nervous
system
(
CNS
)
,
are
a
defining
characteristic
of
GLD
.
Here
we
report
that
exposure
of
primary
glial
cultures
to
psychosine
induces
the
expression
and
the
production
of
matrix
metalloproteinase
(
MMP
)
-
3
that
mediated
a
morphological
transformation
of
microglia
into
a
multinucleated
globoid
cell
type
.
Additionally
,
psychosine-induced
globoid
cell
formation
from
microglia
was
prevented
by
either
genetic
ablation
or
chemical
inhibition
of
MMP-
3
.
These
effects
are
microglia-
specific
as
peripheral
macrophages
exposed
to
psychosine
did
not
become
activated
or
express
increased
levels
of
MMP-
3
.
In
the
brain
from
twitcher
mice
,
a
murine
model
of
human
GLD
,
elevated
MMP-
3
expression
relative
to
wild-
type
littermates
was
contemporaneous
with
disease
onset
and
further
increased
with
disease
progression
.
Further
,
bone
marrow
transplantation
(
BMT
)
,
currently
the
only
therapeutically
beneficial
treatment
for
GLD
,
did
not
mitigate
the
elevated
expression
of
MMP-
3
in
twitcher
mice
.
Hence
,
elevated
expression
of
MMP-
3
in
GLD
may
promote
microglial
responses
to
psychosine
that
may
represent
an
important
pathophysiological
process
in
this
disease
and
its
treatment
.
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