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Persistence of psychosine in brain lipid rafts is a limiting factor in the therapeutic recovery of a mouse model for Krabbe disease.
[krabbe disease]
Sphingolipids
are
intrinsic
components
of
membrane
lipid
rafts
.
The
abnormal
accumulation
of
these
molecules
may
introduce
architectural
and
functional
changes
in
these
domains
,
leading
to
cellular
dysfunction
.
Galactosylsphingosine
(
psychosine
)
is
a
pathogenic
lipid
raft-associated
molecule
whose
accumulation
leads
to
brain
deterioration
and
irreversible
neurological
handicap
in
the
incurable
leukodystrophy
Krabbe
disease
(
KD
)
.
The
relevance
of
clearing
excessive
levels
of
pathogenic
psychosine
from
lipid
rafts
in
therapy
for
KD
has
not
been
investigated
.
The
work
presented
here
demonstrates
that
psychosine
inhibits
raft-mediated
endocytosis
in
neural
cells
.
In
addition
,
although
in
vitro
enzyme
reconstitution
is
sufficient
for
the
reversal
of
related
endocytic
defects
in
affected
neural
cells
,
traditional
in
vivo
enzyme
therapies
in
the
mouse
model
of
KD
appear
to
be
insufficient
for
complete
removal
of
pathogenic
levels
of
raft-associated
psychosine
.
This
work
describes
a
mechanism
that
may
contribute
to
limiting
the
in
vivo
efficacy
of
traditional
therapies
for
KD
.