The Journal of Experimental Medicine,
Год журнала:
2018,
Номер
215(9), С. 2355 - 2377
Опубликована: Авг. 14, 2018
The
progression
of
tau
pathology
in
Alzheimer’s
disease
follows
a
stereotyped
pattern,
and
recent
evidence
suggests
role
synaptic
connections
this
process.
Astrocytes
are
well
positioned
at
the
neuronal
synapse
to
capture
degrade
extracellular
as
it
transits
hence
could
potentially
have
ability
inhibit
spreading
delay
progression.
Our
study
shows
increased
expression
activity
Transcription
Factor
EB
(TFEB),
master
regulator
lysosomal
biogenesis,
response
both
human
brains
with
dementia
transgenic
mouse
models.
Exogenous
TFEB
primary
astrocytes
enhances
fibril
uptake
activity,
while
knockout
has
reverse
effect.
In
vivo,
induced
reduces
hippocampus
PS19
tauopathy
mice,
prominently
attenuates
from
ipsilateral
contralateral
model
spreading.
that
astrocytic
plays
functional
modulating
propagation
tauopathies
such
disease.
Journal of Cell Science,
Год журнала:
2016,
Номер
129(13), С. 2475 - 2481
Опубликована: Июнь 2, 2016
ABSTRACT
The
transcription
factor
EB
(TFEB)
plays
a
pivotal
role
in
the
regulation
of
basic
cellular
processes,
such
as
lysosomal
biogenesis
and
autophagy.
subcellular
localization
activity
TFEB
are
regulated
by
mechanistic
target
rapamycin
(mTOR)-mediated
phosphorylation,
which
occurs
at
surface.
Phosphorylated
is
retained
cytoplasm,
whereas
dephosphorylated
translocates
to
nucleus
induce
genes.
Thus,
lysosome-to-nucleus
signaling
pathway
regulates
energy
metabolism
through
TFEB.
Recently,
vivo
studies
have
revealed
that
also
involved
physiological
lipid
catabolism.
has
attracted
lot
attention
owing
its
ability
intracellular
clearance
pathogenic
factors
variety
murine
models
disease,
Parkinson's
Alzheimer's,
suggesting
novel
therapeutic
strategies
could
be
based
on
modulation
activity.
In
this
Cell
Science
Glance
article
accompanying
poster,
we
present
an
overview
latest
research
function
implication
human
diseases.
Nature Communications,
Год журнала:
2017,
Номер
8(1)
Опубликована: Фев. 6, 2017
Abstract
Neurodegenerative
diseases
characterized
by
aberrant
accumulation
of
undigested
cellular
components
represent
unmet
medical
conditions
for
which
the
identification
actionable
targets
is
urgently
needed.
Here
we
identify
a
pharmacologically
pathway
that
controls
clearance
via
Akt
modulation
transcription
factor
EB
(TFEB),
master
regulator
lysosomal
pathways.
We
show
phosphorylates
TFEB
at
Ser467
and
represses
nuclear
translocation
independently
mechanistic
target
rapamycin
complex
1
(mTORC1),
known
inhibitor.
The
autophagy
enhancer
trehalose
activates
diminishing
activity.
Administration
to
mouse
model
Batten
disease,
prototypical
neurodegenerative
disease
presenting
with
intralysosomal
storage,
enhances
proteolipid
aggregates,
reduces
neuropathology
prolongs
survival
diseased
mice.
Pharmacological
inhibition
promotes
in
cells
from
patients
variety
diseases,
thus
suggesting
broad
applicability
this
approach.
These
findings
open
new
perspectives
clinical
translation
TFEB-mediated
enhancement
storage
diseases.
