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Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation.
[wiskott-aldrich syndrome]
Retromer
is
a
protein
assembly
that
plays
a
central
role
in
orchestrating
export
of
transmembrane-spanning
cargo
proteins
from
endosomes
into
retrieval
pathways
destined
for
the
Golgi
apparatus
and
the
plasma
membrane
[
1
]
.
Recently
,
a
specific
mutation
in
the
retromer
component
VPS
35
,
VPS
35
(
D
620
N
)
,
has
linked
retromer
dysfunction
to
familial
autosomal
dominant
and
sporadic
Parkinson
disease
[
2
,
3
]
.
However
,
the
effect
of
this
mutation
on
retromer
function
remains
poorly
characterized
.
Here
we
established
that
in
cells
expressing
VPS
35
(
D
620
N
)
there
is
a
perturbation
in
endosome-
to
-
TGN
transport
but
not
endosome-
to
-plasma
membrane
recycling
,
which
we
confirm
in
patient
cells
harboring
the
VPS
35
(
D
620
N
)
mutation
.
Through
comparative
stable
isotope
labeling
by
amino
acids
in
cell
culture
(
SILAC
)
-
based
analysis
of
wild-
type
VPS
35
versus
the
VPS
35
(
D
620
N
)
mutant
interactomes
,
we
establish
that
the
major
defect
of
the
D
620
N
mutation
lies
in
the
association
to
the
actin-nucleating
Wiskott-
Aldrich
syndrome
and
SCAR
homolog
(
WASH
)
complex
.
Moreover
,
using
isothermal
calorimetry
,
we
establish
that
the
primary
defect
of
the
VPS
35
(
D
620
N
)
mutant
is
a
2
.
2
±
0
.
5
-
fold
decrease
in
affinity
for
the
WASH
complex
component
FAM
21
.
These
data
define
the
primary
molecular
defect
in
retromer
assembly
that
arises
from
the
VPS
35
(
D
620
N
)
mutation
and
,
by
revealing
functional
effects
on
retromer-mediated
endosome-
to
-
TGN
transport
,
provide
new
insight
into
retromer
deregulation
in
Parkinson
disease
.
Diseases
Validation
Diseases presenting
"defect of the vps35(d620n) mutant"
symptom
wiskott-aldrich syndrome
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