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Oligomers of mutant glial fibrillary acidic protein (GFAP) Inhibit the proteasome system in alexander disease astrocytes, and the small heat shock protein alphaB-crystallin reverses the inhibition.
[alexander disease]
The
accumulation
of
the
intermediate
filament
protein
,
glial
fibrillary
acidic
protein
(
GFAP
)
,
in
astrocytes
of
Alexander
disease
(
AxD
)
impairs
proteasome
function
in
astrocytes
.
We
have
explored
the
molecular
mechanism
that
underlies
the
proteasome
inhibition
.
We
find
that
both
assembled
and
unassembled
wild
type
(
wt
)
and
R
239
C
mutant
GFAP
protein
interacts
with
the
20
S
proteasome
complex
and
that
the
R
239
C
AxD
mutation
does
not
interfere
with
this
interaction
.
However
,
the
R
239
C
GFAP
accumulates
to
higher
levels
and
forms
more
protein
aggregates
than
wt
protein
.
These
aggregates
bind
components
of
the
ubiquitin-proteasome
system
and
,
thus
,
may
deplete
the
cytosolic
stores
of
these
proteins
.
We
also
find
that
the
R
239
C
GFAP
has
a
greater
inhibitory
effect
on
proteasome
system
than
wt
GFAP
.
Using
a
ubiquitin-independent
degradation
assay
in
vitro
,
we
observed
that
the
proteasome
can
not
efficiently
degrade
unassembled
R
239
C
GFAP
,
and
the
interaction
of
R
239
C
GFAP
with
proteasomes
actually
inhibits
proteasomal
protease
activity
.
The
small
heat
shock
protein
,
alphaB-crystallin
,
which
accumulates
massively
in
AxD
astrocytes
,
reverses
the
inhibitory
effects
of
R
239
C
GFAP
on
proteasome
activity
and
promotes
degradation
of
the
mutant
GFAP
,
apparently
by
shifting
the
size
of
the
mutant
protein
from
larger
oligomers
to
smaller
oligomers
and
monomers
.
These
observations
suggest
that
oligomeric
forms
of
GFAP
are
particularly
effective
at
inhibiting
proteasome
activity
.
Diseases
Validation
Diseases presenting
"small heat shock protein"
symptom
alexander disease
hereditary cerebral hemorrhage with amyloidosis
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