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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
"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