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Role of endogenous psychosine accumulation in oligodendrocyte differentiation and survival: implication for Krabbe disease.
[krabbe disease]
Krabbe
disease
is
a
lethal
,
demyelinating
condition
caused
by
genetic
deficiency
of
galactocerebrosidase
(
GALC
)
and
resultant
accumulation
of
its
cytotoxic
substrate
,
psychosine
(
galactosylsphingosine
)
,
primarily
in
oligodendrocytes
(
OLs
)
.
Psychosine
is
generated
by
galactosylation
of
sphingosine
by
UDP-galactose
:
ceramide
galactosyltransferase
(
CGT
)
,
a
galactosylceramide
synthesizing
enzyme
which
is
primarily
expressed
in
OLs
.
The
expression
of
CGT
and
the
synthesis
of
galactosyl-sphingolipids
are
associated
with
the
terminal
differentiation
of
OL
,
but
little
is
known
about
the
participation
of
endogenous
psychosine
accumulation
in
OL
differentiation
under
GALC
deficient
conditions
.
In
this
study
,
we
report
that
accumulation
of
endogenous
psychosine
under
GALC
deficient
Krabbe
conditions
impedes
OL
differentiation
process
both
by
decreasing
the
expression
of
myelin
lipids
and
protein
and
by
inducing
the
cell
death
of
maturating
OLs
.
The
psychosine
pathology
under
GALC
deficient
conditions
involves
participation
of
secretory
phospholipase
A
2
(
sPLA
2
)
activation
and
increase
in
its
metabolites
,
as
evidenced
by
attenuation
of
psychosine-induced
pathology
by
treatment
with
pharmacological
inhibitor
of
sPLA
2
7
,
7
-
dimethyleicosadienoic
acid
(
DEDA
)
.
These
observations
suggest
for
potential
therapeutic
efficacy
of
sPLA
2
inhibitor
in
Krabbe
disease
.
