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Molecular mechanisms of pathogenesis in a glycosphingolipid and a glycoprotein storage disease.
[gm1 gangliosidosis]
The
lysosomal
system
comprises
a
specialized
network
of
organelles
crucial
for
the
sorting
,
digestion
,
recycling
and
secretion
of
cellular
components
.
With
their
content
of
hydrolytic
enzymes
,
lysosomes
regulate
the
degradation
of
a
multitude
of
substrates
that
reach
these
organelles
via
the
biosynthetic
or
the
endocytic
route
.
Gene
defects
that
affect
one
or
more
of
these
hydrolases
lead
to
LSDs
(
lysosomal
storage
diseases
)
.
This
underscores
the
apparent
lack
of
redundancy
of
these
enzymes
and
the
importance
of
the
lysosomal
system
in
cell
and
tissue
homoeostasis
.
Some
of
the
lysosomal
enzymes
may
form
multiprotein
complexes
,
which
usually
work
synergistically
on
substrates
and
,
in
this
configuration
,
may
respond
more
efficiently
to
changes
in
substrate
load
and
composition
.
A
well-characterized
lysosomal
multienzyme
complex
is
the
one
comprising
the
glycosidases
β-gal
(
β-galactosidase
)
and
NEU
1
(
neuramidase-
1
)
,
and
of
the
serine
carboxypeptidase
PPCA
(
protective
protein
/
cathepsin
A
)
.
Three
neurodegenerative
LSDs
are
caused
by
either
single
or
combined
deficiency
of
these
lysosomal
enzymes
.
Sialidosis
(
NEU
1
deficiency
)
and
galactosialidosis
(
combined
NEU
1
and
β-gal
deficiency
,
secondary
to
a
primary
defect
of
PPCA
)
belong
to
the
glycoprotein
storage
diseases
,
whereas
GM
1
-
gangliosidosis
(
β-gal
deficiency
)
is
a
glycosphingolipid
storage
disease
.
Identification
of
novel
molecular
pathways
that
are
deregulated
because
of
loss
of
enzyme
activity
and
/
or
accumulation
of
specific
metabolites
in
various
cell
types
has
shed
light
on
mechanisms
of
disease
pathogenesis
and
may
pave
the
way
for
future
development
of
new
therapies
for
these
LSDs
.
