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Psychosine, the cytotoxic sphingolipid that accumulates in globoid cell leukodystrophy, alters membrane architecture.
[krabbe disease]
Globoid
cell
leukodystrophy
(
GLD
)
is
a
neurological
disease
caused
by
deficiency
of
the
lysosomal
enzyme
galactosylceramidase
(
GALC
)
.
In
the
absence
of
GALC
,
the
cytotoxic
glycosphingolipid
,
psychosine
(
psy
)
,
accumulates
in
the
nervous
system
.
Psychosine
accumulation
preferentially
affects
oligodendrocytes
,
leading
to
progressive
demyelination
and
infiltration
of
activated
monocytes
/
macrophages
into
the
CNS
.
GLD
is
characterized
by
motor
defects
,
cognitive
deficits
,
seizures
,
and
death
by
2
-
5
years
of
age
.
It
has
been
hypothesized
that
psychosine
accumulation
,
primarily
within
lipid
rafts
,
results
in
the
pathogenic
cascade
in
GLD
.
However
,
the
mechanism
of
psychosine
toxicity
has
yet
to
be
elucidated
.
Therefore
,
we
synthesized
the
enantiomer
of
psychosine
(
ent-psy
)
to
use
as
a
probe
to
distinguish
between
protein-psy
(
stereo-
specific
enantioselective
)
or
membrane-psy
(
stereo-insensitive
nonenantioselective
)
interactions
.
The
enantiomer
of
psychosine
has
equal
or
greater
toxicity
compared
with
psy
,
suggesting
that
psy
exerts
its
toxicity
through
a
nonenantioselective
mechanism
.
Finally
,
in
this
study
we
demonstrate
that
psy
and
ent-psy
localize
to
lipid
rafts
,
perturb
natural
and
artificial
membrane
integrity
,
and
inhibit
protein
Kinase
C
translocation
to
the
plasma
membrane
.
Although
other
mechanisms
may
play
a
role
in
disease
,
these
data
strongly
suggest
that
psy
exerts
its
effects
primarily
through
membrane
perturbation
rather
than
through
specific
protein-psy
interactions
.
Diseases
Validation
Diseases presenting
"progressive demyelination"
symptom
adrenomyeloneuropathy
krabbe disease
x-linked adrenoleukodystrophy
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