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Psychosine induces the dephosphorylation of neurofilaments by deregulation of PP1 and PP2A phosphatases.
[krabbe disease]
Patients
with
Krabbe
disease
,
a
genetic
demyelinating
syndrome
caused
by
deficiency
of
galactosyl-ceramidase
and
the
resulting
accumulation
of
galactosyl-sphingolipids
,
develop
signs
of
a
dying-back
axonopathy
compounded
by
a
deficiency
of
large
-caliber
axons
.
Here
,
we
show
that
axonal
caliber
in
Twitcher
mice
,
an
animal
model
for
Krabbe
disease
,
is
impaired
in
peripheral
axons
and
is
accompanied
by
a
progressive
reduction
in
the
abundance
and
phosphorylation
of
the
three
neurofilament
(
NF
)
subunits
.
These
changes
correlate
with
an
increase
in
the
density
of
NFs
per
cross-sectional
area
in
numerous
mutant
peripheral
axons
and
abnormal
increases
in
the
activity
of
two
serine
/
threonine
phosphatases
(
PP
1
and
PP
2
A
)
in
mutant
tissue
.
Similarly
,
acutely
isolated
mutant
cortical
neurons
show
abnormal
phosphorylation
of
NFs
.
Psychosine
,
the
neurotoxin
accumulated
in
Krabbe
disease
,
was
sufficient
to
induce
abnormal
dephosphorylation
of
NF
subunits
in
a
normal
motor
neuron
cell
line
as
well
as
in
acutely
isolated
normal
cortical
neurons
.
This
in
vitro
effect
was
mediated
by
PP
1
and
PP
2
A
,
which
specifically
dephosphorylated
NFs
.
These
results
demonstrate
that
the
reduced
caliber
observed
in
some
axons
in
Krabbe
disease
involves
abnormal
dephosphorylation
of
NFs
.
We
propose
that
a
psychosine-driven
pathogenic
mechanism
through
deregulated
phosphotransferase
activities
may
be
involved
in
this
process
.
Diseases
Validation
Diseases presenting
"abnormal phosphorylation"
symptom
krabbe disease
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