Journal of Biological Chemistry,
Journal Year:
2013,
Volume and Issue:
288(21), P. 15194 - 15210
Published: March 27, 2013
Cytoplasmic
α-synuclein
(α-syn)
aggregates,
referred
to
as
Lewy
bodies,
are
pathological
hallmarks
of
a
number
neurodegenerative
diseases,
most
notably
Parkinson
disease.
Activation
macroautophagy
is
suggested
facilitate
degradation
certain
proteinaceous
inclusions,
but
it
unclear
if
this
pathway
capable
degrading
α-syn
aggregates.
Here,
we
examined
issue
by
utilizing
cellular
models
in
which
intracellular
body-like
inclusions
accumulate
after
internalization
pre-formed
fibrils
into
α-syn-expressing
HEK293
cells
or
cultured
primary
neurons.
We
demonstrate
that
cannot
be
effectively
degraded,
even
though
they
co-localize
with
essential
components
both
the
autophagic
and
proteasomal
protein
pathways.
The
aggregates
persist
soluble
levels
have
been
substantially
reduced,
suggesting
once
formed,
refractory
clearance.
Importantly,
also
find
impair
overall
reducing
autophagosome
clearance,
may
contribute
increased
cell
death
observed
aggregate-bearing
cells.
Proceedings of the National Academy of Sciences,
Journal Year:
2013,
Volume and Issue:
110(19)
Published: April 22, 2013
Significance
This
study
shows
that
neurodegenerative
changes
induced
by
α-synuclein
in
midbrain
dopamine
neurons
vivo
can
be
blocked
through
activation
of
the
autophagy-lysosome
pathway.
Using
an
adeno-associated
virus
model
Parkinson
disease
to
overexpress
substantia
nigra,
we
show
genetic
[transcription
factor
EB
(TFEB)
and
Beclin-1
overexpression]
or
pharmacological
(rapalog)
manipulations
enhance
autophagy
protect
nigral
from
toxicity,
but
inhibiting
exacerbates
toxicity.
The
results
provide
a
mechanistic
link
between
toxicity
impaired
TFEB
function,
identify
as
target
for
therapies
aimed
at
neuroprotection
modification
disease.
Progress in Neurobiology,
Journal Year:
2013,
Volume and Issue:
108, P. 21 - 43
Published: July 11, 2013
Alzheimer's
disease
(AD)
is
an
age-related
devastating
neurodegenerative
disorder,
which
severely
impacts
on
the
global
economic
development
and
healthcare
system.
Though
AD
has
been
studied
for
more
than
100
years
since
1906,
exact
cause(s)
pathogenic
mechanism(s)
remain
to
be
clarified.
Also,
efficient
disease-modifying
treatment
ideal
diagnostic
method
are
unavailable.
Perturbed
cerebral
glucose
metabolism,
invariant
pathophysiological
feature
of
AD,
may
a
critical
contributor
pathogenesis
this
disease.
In
review,
we
firstly
discussed
features
metabolism
in
physiological
pathological
conditions.
Then,
further
reviewed
contribution
transportation
abnormality
intracellular
catabolism
dysfunction
pathophysiology,
proposed
hypothesis
that
multiple
cascades
induced
by
impaired
could
result
neuronal
degeneration
consequently
cognitive
deficits
patients.
Among
these
processes,
altered
functional
status
thiamine
brain
insulin
resistance
highly
emphasized
characterized
as
major
mechanisms.
Finally,
considering
fact
patients
exhibit
hypometabolism
possibly
due
impairments
signaling
also
discuss
some
potential
possibilities
uncover
biomarkers
from
abnormal
develop
drugs
targeting
at
repairing
impairment
correcting
abnormality.
We
conclude
plays
role
alterations
through
induction
factors
such
oxidative
stress,
mitochondrial
dysfunction,
so
forth.
To
clarify
causes,
pathogeneses
consequences
will
help
break
bottleneck
current
study
finding
biomarker
therapy.
