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The effect of N-acetyl-aspartyl-glutamate and N-acetyl-aspartate on white matter oligodendrocytes.
[canavan disease]
Elevations
of
the
levels
of
N-
acetyl-aspartyl-glutamate
(
NAAG
)
and
N-
acetyl-aspartate
(
NAA
)
are
associated
with
myelin
loss
in
the
leucodystrophies
Canavan
's
disease
and
Pelizaeus-
Merzbacher-like
disease
.
NAAG
and
NAA
can
activate
and
antagonize
neuronal
N-
methyl-
D-
aspartate
(
NMDA
)
receptors
,
and
also
act
on
group
II
metabotropic
glutamate
receptors
.
Oligodendrocytes
and
their
precursors
have
recently
been
shown
to
express
NMDA
receptors
,
and
activation
of
these
receptors
in
ischaemia
leads
to
the
death
of
oligodendrocyte
precursors
and
the
loss
of
myelin
.
This
raises
the
possibility
that
the
failure
to
develop
myelin
,
or
demyelination
,
occurring
in
the
leucodystrophies
could
reflect
an
action
of
NAAG
or
NAA
on
oligodendrocyte
NMDA
receptors
.
However
,
since
the
putative
subunit
composition
of
NMDA
receptors
on
oligodendrocytes
differs
from
that
of
neuronal
NMDA
receptors
,
the
effects
of
NAAG
and
NAA
on
them
are
unknown
.
We
show
that
NAAG
,
but
not
NAA
,
evokes
an
inward
membrane
current
in
cerebellar
white
matter
oligodendrocytes
,
which
is
reduced
by
NMDA
receptor
block
(
but
not
by
block
of
metabotropic
glutamate
receptors
)
.
The
size
of
the
current
evoked
by
NAAG
,
relative
to
that
evoked
by
NMDA
,
was
much
smaller
in
oligodendrocytes
than
in
neurons
,
and
NAAG
induced
a
rise
in
[
Ca
(
2
+
)
]
(
i
)
in
neurons
but
not
in
oligodendrocytes
.
These
differences
in
the
effect
of
NAAG
on
oligodendrocytes
and
neurons
may
reflect
the
aforementioned
difference
in
receptor
subunit
composition
.
In
addition
,
as
a
major
part
of
the
response
in
oligodendrocytes
was
blocked
by
tetrodotoxin
(
TTX
)
,
much
of
the
NAAG-evoked
current
in
oligodendrocytes
is
a
secondary
consequence
of
activating
neuronal
NMDA
receptors
.
Six
hours
exposure
to
1
mM
NAAG
did
not
lead
to
the
death
of
cells
in
the
white
matter
.
We
conclude
that
an
action
of
NAAG
on
oligodendrocyte
NMDA
receptors
is
unlikely
to
be
a
major
contributor
to
white
matter
damage
in
the
leucodystrophies
.
Diseases
Validation
Diseases presenting
"occurring in the leucodystrophies could reflect an action of naag or naa on oligodendrocyte nmda receptors"
symptom
canavan disease
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