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Lysosomal accumulation of Trk protein in brain of GMâ‚ -gangliosidosis mouse and its restoration by chemical chaperone.
[gm1 gangliosidosis]
G
(
M
1
)
-
gangliosidosis
is
a
fatal
neurodegenerative
disorder
caused
by
deficiency
of
lysosomal
acid
β-galactosidase
(
β-gal
)
.
Accumulation
of
its
substrate
ganglioside
G
(
M
1
)
(
G
(
M
1
)
)
in
lysosomes
and
other
parts
of
the
cell
leads
to
progressive
neurodegeneration
,
but
underlying
mechanisms
remain
unclear
.
Previous
studies
demonstrated
an
essential
role
for
interaction
of
G
(
M
1
)
with
tropomyosin
receptor
kinase
(
Trk
)
receptors
in
neuronal
growth
,
survival
and
differentiation
.
In
this
study
we
demonstrate
accumulation
of
G
(
M
1
)
in
the
cell-surface
rafts
and
lysosomes
of
the
β-gal
knockout
(
β-gal-
/
-
)
mouse
brain
association
with
accumulation
of
Trk
receptors
and
enhancement
of
its
downstream
signaling
.
Immunofluorescence
and
subcellular
fractionation
analysis
revealed
accumulation
of
Trk
receptors
in
the
late
endosomes
/
lysosomes
of
the
β-gal-
/
-
mouse
brain
and
their
association
with
ubiquitin
and
p
62
.
Administration
of
a
chemical
chaperone
to
β-gal-
/
-
mouse
expressing
human
mutant
R
201
C
protein
resulted
in
a
marked
reduction
of
intracellular
storage
of
G
(
M
1
)
and
phosphorylated
Trk
.
These
findings
indicate
that
G
(
M
1
)
accumulation
in
rafts
causes
activation
of
Trk
signaling
,
which
may
participate
in
the
pathogenesis
of
G
(
M
1
)
-
gangliosidosis
.
Diseases
Validation
Diseases presenting
"marked reduction of intracellular storage"
symptom
gm1 gangliosidosis
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