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Loss of Oca2 disrupts the unfolded protein response and increases resistance to endoplasmic reticulum stress in melanocytes.
[oculocutaneous albinism]
Accumulation
of
proteins
in
the
endoplasmic
reticulum
(
ER
)
typically
induces
stress
and
initiates
the
unfolded
protein
response
(
UPR
)
to
facilitate
recovery
.
If
homeostasis
is
not
restored
,
apoptosis
is
induced
.
However
,
adaptation
to
chronic
UPR
activation
can
increase
resistance
to
subsequent
acute
ER
stress
.
We
therefore
investigated
adaptive
mechanisms
in
Oculocutaneous
albinism
type
2
(
Oca
2
)
-
null
melanocytes
where
UPR
signaling
is
arrested
despite
continued
tyrosinase
accumulation
leading
to
resistance
to
the
chemical
ER
stressor
thapsigargin
.
Although
thapsigargin
triggers
UPR
activation
,
instead
of
Perk-mediated
phosphorylation
of
eIF
2
α
,
in
Oca
2
-
null
melanocytes
,
eIF
2
α
was
rapidly
dephosphorylated
upon
treatment
.
Dephosphorylation
was
mediated
by
the
Gadd
34
-
PP
1
α
phosphatase
complex
.
Gadd
34
-
complex
inhibition
blocked
eIF
2
α
dephosphorylation
and
significantly
increased
Oca
2
-
null
melanocyte
sensitivity
to
thapsigargin
.
Thus
,
Oca
2
-
null
melanocytes
adapt
to
acute
ER
stress
by
disruption
of
pro-apoptotic
Perk
signaling
,
which
promotes
cell
survival
.
This
is
the
first
study
to
demonstrate
rapid
eIF
2
α
dephosphorylation
as
an
adaptive
mechanism
to
ER
stress
.
Diseases
Validation
Diseases presenting
"first study"
symptom
achondroplasia
acute rheumatic fever
alexander disease
aniridia
coats disease
congenital adrenal hyperplasia
cowden syndrome
dystrophic epidermolysis bullosa
erythropoietic protoporphyria
familial hypocalciuric hypercalcemia
familial mediterranean fever
heparin-induced thrombocytopenia
hirschsprung disease
krabbe disease
locked-in syndrome
oculocutaneous albinism
primary effusion lymphoma
waldenström macroglobulinemia
wiskott-aldrich syndrome
zellweger syndrome
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