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Mechanisms of distribution of mouse beta-galactosidase in the adult GM1-gangliosidosis brain.
[gm1 gangliosidosis]
GM
1
-
gangliosidosis
is
a
lysosomal
storage
disease
(
LSD
)
caused
by
an
autosomal
recessive
deficiency
of
lysosomal
acid
beta
-galactosidase
(
betagal
)
.
This
leads
to
accumulation
of
GM
1
-
ganglioside
and
its
asialo
derivative
GA
1
in
the
central
nervous
system
(
CNS
)
,
and
progressive
neurodegeneration
.
Therapeutic
AAV-mediated
gene
delivery
to
the
brain
for
LSDs
has
proven
very
successful
in
several
animal
models
.
GM
1
-
gangliosidosis
is
also
a
prime
candidate
for
AAV-mediated
gene
therapy
in
the
CNS
.
As
global
neuropathology
characterizes
the
most
severe
forms
of
this
disease
,
therapeutic
interventions
need
to
achieve
distribution
of
betagal
throughout
the
entire
CNS
.
Therefore
,
careful
consideration
of
routes
of
administration
and
target
structures
from
where
metabolically
active
enzyme
can
be
produced
,
released
and
distributed
throughout
the
CNS
,
is
necessary
.
The
goal
of
this
study
was
to
investigate
the
pattern
and
mechanism
of
distribution
of
betagal
in
the
adult
GM
1
-
gangliosidosis
mouse
brain
upon
hippocampal
injection
of
an
AAV
vector-encoding
betagal
.
We
found
evidence
that
three
different
mechanisms
contribute
to
its
distribution
in
the
brain
:
(
1
)
diffusion
;
(
2
)
axonal
transport
within
neurons
from
the
site
of
production
;
(
3
)
CSF
flow
in
the
perivascular
space
of
Virchow-
Robin
.
In
addition
,
we
found
evidence
of
axonal
transport
of
vector-encoded
mRNA
.
Diseases
Validation
Diseases presenting
"progressive neurodegeneration"
symptom
gm1 gangliosidosis
triple a syndrome
This symptom has already been validated