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Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy.
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Polyglutamine
pathologies
are
neurodegenerative
diseases
that
manifest
both
general
polyglutamine
toxicity
and
mutant
protein-
specific
effects
.
Dentatorubral-pallidoluysian
Atrophy
(
DRPLA
)
is
one
of
these
disorders
caused
by
mutations
in
the
Atrophin-
1
protein
.
We
have
generated
several
models
for
DRPLA
in
Drosophila
and
analysed
the
mechanisms
of
cellular
and
organism
toxicity
.
Our
genetic
and
ultrastructural
analysis
of
neurodegeneration
suggests
that
autophagy
may
have
a
role
in
cellular
degeneration
when
polyglutamine
proteins
are
overexpressed
in
neuronal
and
glial
cells
.
Clearance
of
autophagic
organelles
is
blocked
at
the
lysosomal
level
after
correct
fusion
between
autophagosomes
and
lysosomes
.
This
leads
to
accumulation
of
autofluorescent
pigments
and
proteinaceous
residues
usually
degraded
by
the
autophagy-lysosome
system
.
Under
these
circumstances
,
further
pharmacological
and
genetic
induction
of
autophagy
does
not
rescue
neurodegeneration
by
polyglutamine
Atrophins
,
in
contrast
to
many
other
neurodegenerative
conditions
.
Our
data
thus
provide
a
crucial
insight
into
the
specific
mechanism
of
a
polyglutamine
disease
and
reveal
important
differences
in
the
role
of
autophagy
with
respect
to
other
diseases
of
the
same
family
.
