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Gangliosides and gangliosidoses: principles of molecular and metabolic pathogenesis.
[gm1 gangliosidosis]
Gangliosides
are
the
main
glycolipids
of
neuronal
plasma
membranes
.
Their
surface
patterns
are
generated
by
coordinated
processes
,
involving
biosynthetic
pathways
of
the
secretory
compartments
,
catabolic
steps
of
the
endolysosomal
system
,
and
intracellular
trafficking
.
Inherited
defects
in
ganglioside
biosynthesis
causing
fatal
neurodegenerative
diseases
have
been
described
so
far
almost
exclusively
in
mouse
models
,
whereas
inherited
defects
in
ganglioside
catabolism
causing
various
clinical
forms
of
GM
1
-
and
GM
2
-
gangliosidoses
have
long
been
known
.
For
digestion
,
gangliosides
are
endocytosed
and
reach
intra-endosomal
vesicles
.
At
the
level
of
late
endosomes
,
they
are
depleted
of
membrane-stabilizing
lipids
like
cholesterol
and
enriched
with
bis
(
monoacylglycero
)
phosphate
(
BMP
)
.
Lysosomal
catabolism
is
catalyzed
at
acidic
pH
values
by
cationic
sphingolipid
activator
proteins
(
SAPs
)
,
presenting
lipids
to
their
respective
hydrolases
,
electrostatically
attracted
to
the
negatively
charged
surface
of
the
luminal
BMP-rich
vesicles
.
Various
inherited
defects
of
ganglioside
hydrolases
,
e
.
g
.
,
of
β-galactosidase
and
β-hexosaminidases
,
and
of
GM
2
-
activator
protein
,
cause
infantile
(
with
tetraparesis
,
dementia
,
blindness
)
and
different
protracted
clinical
forms
of
GM
1
-
and
GM
2
-
gangliosidoses
.
Mutations
yielding
proteins
with
small
residual
catabolic
activities
in
the
lysosome
give
rise
to
juvenile
and
adult
clinical
forms
with
a
wide
range
of
clinical
symptomatology
.
Apart
from
patients
'
differences
in
their
genetic
background
,
clinical
heterogeneity
may
be
caused
by
rather
diverse
substrate
specificities
and
functions
of
lysosomal
hydrolases
,
multifunctional
properties
of
SAPs
,
and
the
strong
regulation
of
ganglioside
catabolism
by
membrane
lipids
.
Currently
,
there
is
no
treatment
available
for
neuronal
ganglioside
storage
diseases
.
Therapeutic
approaches
in
mouse
models
and
patients
with
juvenile
forms
of
gangliosidoses
are
discussed
.
Diseases
Validation
Diseases presenting
"negatively charged surface of the luminal"
symptom
gm1 gangliosidosis
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