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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
.
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symptom
aromatase deficiency
cushing syndrome
holt-oram syndrome
junctional epidermolysis bullosa
krabbe disease
triple a syndrome
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