Science Signaling,
Journal Year:
2024,
Volume and Issue:
17(829)
Published: March 26, 2024
Mutations
in
the
gene
encoding
lysosomal
enzyme
glucocerebrosidase
(GCase)
are
responsible
for
Gaucher
disease
(GD)
and
considered
strongest
genetic
risk
factor
Parkinson’s
(PD)
Lewy
body
dementia
(LBD).
GCase
deficiency
leads
to
extensive
accumulation
of
glucosylceramides
(GCs)
cells
contributes
neuropathology
GD,
PD,
LBD
by
triggering
chronic
neuroinflammation.
Here,
we
investigated
mechanisms
which
GC
induces
We
found
that
within
microglia
induced
pharmacological
inhibition
triggered
STING-dependent
inflammation,
contributed
neuronal
loss
both
vitro
vivo.
mitochondrial
DNA
(mtDNA)
leakage
cytosol
trigger
inflammation.
Rapamycin,
a
compound
promotes
activity,
improved
function,
thereby
decreasing
STING
signaling.
Furthermore,
damage
caused
led
defects
degradation
activated
STING,
further
exacerbating
inflammation
mediated
microglia.
Thus,
limiting
activity
may
be
strategy
suppress
neuroinflammation
deficiency.
Signal Transduction and Targeted Therapy,
Journal Year:
2023,
Volume and Issue:
8(1)
Published: July 12, 2023
Abstract
Studies
in
neurodegenerative
diseases,
including
Alzheimer’s
disease,
Parkinson’s
disease
and
Amyotrophic
lateral
sclerosis,
Huntington’s
so
on,
have
suggested
that
inflammation
is
not
only
a
result
of
neurodegeneration
but
also
crucial
player
this
process.
Protein
aggregates
which
are
very
common
pathological
phenomenon
can
induce
neuroinflammation
further
aggravates
protein
aggregation
neurodegeneration.
Actually,
even
happens
earlier
than
aggregation.
Neuroinflammation
induced
by
genetic
variations
CNS
cells
or
peripheral
immune
may
deposition
some
susceptible
population.
Numerous
signaling
pathways
range
been
to
be
involved
the
pathogenesis
neurodegeneration,
although
they
still
far
from
being
completely
understood.
Due
limited
success
traditional
treatment
methods,
blocking
enhancing
inflammatory
considered
promising
strategies
for
therapy
many
them
got
exciting
results
animal
models
clinical
trials.
Some
them,
few,
approved
FDA
usage.
Here
we
comprehensively
review
factors
affecting
major
pathogenicity
sclerosis.
We
summarize
current
strategies,
both
clinic,
diseases.
Nature,
Journal Year:
2023,
Volume and Issue:
620(7973), P. 374 - 380
Published: Aug. 2, 2023
Low-grade
inflammation
is
a
hallmark
of
old
age
and
central
driver
ageing-associated
impairment
disease1.
Multiple
factors
can
contribute
to
inflammation2;
however,
the
molecular
pathways
that
transduce
aberrant
inflammatory
signalling
their
impact
in
natural
ageing
remain
unclear.
Here
we
show
cGAS-STING
pathway,
which
mediates
immune
sensing
DNA3,
critical
chronic
functional
decline
during
ageing.
Blockade
STING
suppresses
phenotypes
senescent
human
cells
tissues,
attenuates
ageing-related
multiple
peripheral
organs
brain
mice,
leads
an
improvement
tissue
function.
Focusing
on
brain,
reveal
activation
triggers
reactive
microglial
transcriptional
states,
neurodegeneration
cognitive
decline.
Cytosolic
DNA
released
from
perturbed
mitochondria
elicits
cGAS
activity
microglia,
defining
mechanism
by
engaged
brain.
Single-nucleus
RNA-sequencing
analysis
microglia
hippocampi
gain-of-function
mouse
model
demonstrates
engagement
sufficient
direct
states
leading
bystander
cell
inflammation,
neurotoxicity
impaired
memory
capacity.
Our
findings
establish
pathway
as
blockade
potential
strategy
halt
neurodegenerative
processes
age.
Frontiers in Immunology,
Journal Year:
2022,
Volume and Issue:
13
Published: July 22, 2022
Neurological
disorders
(NDs)
are
one
of
the
leading
causes
global
death.
A
sustained
neuroinflammatory
response
has
been
reported
to
be
associated
with
pathogenesis
multiple
NDs,
including
Parkinson’s
disease
(PD),
sclerosis
(MS),
Alzheimer’s
(AD),
amyotrophic
lateral
(ALS),
and
major
depressive
disorder
(MDD).
Accumulating
evidence
shows
that
recruitment
abundant
lymphocytes
in
central
nervous
system
may
contribute
promoting
development
progress
inflammation
neurological
disorders.
As
subset
T
lymphocytes,
CD4
+
cells
have
a
critical
impact
on
helper
(Th)
17
is
most
studied
Th
subpopulations
produces
cytokines
(e.g.,
IL-17A,
IL-23,
IL-21,
IL-6,
IFN-γ),
abnormal
excessive
activation
microglia
other
immune
cell
types.
All
these
factors
involved
several
However,
possible
mechanisms
Th17
their
immunopathology
abovementioned
not
clarified
completely.
This
review
will
summarize
by
which
encephalitogenic
inflammatory
related
strongly
chronic
neuroinflammation,
thus
perpetuating
neurodegenerative
processes
NDs.
Finally,
potential
therapeutic
prospects
NDs
also
discussed.
The Journal of Experimental Medicine,
Journal Year:
2023,
Volume and Issue:
220(3)
Published: Jan. 13, 2023
The
cGAS-STING
pathway
is
an
evolutionarily
conserved
immune
signaling
critical
for
microbial
defense.
Unlike
other
innate
pathways
that
largely
rely
on
stationary
cascades
of
events,
STING
highly
mobile
in
the
cell.
activated
ER,
but
only
signals
after
it
arrives
Golgi,
and
then
quickly
degraded
by
lysosome.
Each
step
trafficking
through
secretory
regulated
host
factors.
Homeostatic
via
COPI-,
COPII-,
clathrin-coated
vesicles
important
maintaining
baseline
tissue
cellular
immunity.
Aberrant
vesicular
or
lysosomal
dysfunction
produces
signal
STING,
which
often
leads
to
pathology
mice
humans.
Many
trafficking-mediated
diseases
appear
impact
central
nervous
system,
leading
neurodegeneration.
Therefore,
introduces
a
new
dimension
likely
has
broad
implications
human
disease.
Molecular Neurodegeneration,
Journal Year:
2023,
Volume and Issue:
18(1)
Published: Nov. 8, 2023
Abstract
DNA
sensing
is
a
pivotal
component
of
the
innate
immune
system
that
responsible
for
detecting
mislocalized
and
triggering
downstream
inflammatory
pathways.
Among
sensors,
cyclic
GMP-AMP
synthase
(cGAS)
primary
player
in
cytosolic
DNA,
including
foreign
from
pathogens
self-DNA
released
during
cellular
damage,
culminating
type
I
interferon
(IFN-I)
response
through
stimulator
genes
(STING)
activation.
IFN-I
cytokines
are
essential
mediating
neuroinflammation,
which
widely
observed
CNS
injury,
neurodegeneration,
aging,
suggesting
an
upstream
role
cGAS
pathway.
In
this
review,
we
summarize
latest
developments
on
cGAS-STING
DNA-driven
various
neurological
diseases
conditions.
Our
review
covers
current
understanding
molecular
mechanisms
activation
highlights
signaling
cell
types
central
peripheral
nervous
systems,
such
as
resident
brain
cells,
neurons,
glial
cells.
We
then
discuss
different
neurodegenerative
conditions,
tauopathies,
Alzheimer’s
disease,
Parkinson’s
amyotrophic
lateral
sclerosis,
well
aging
senescence.
Finally,
lay
out
advancements
research
development
inhibitors
assess
prospects
targeting
STING
therapeutic
strategies
wide
spectrum
diseases.
International Journal of Molecular Medicine,
Journal Year:
2024,
Volume and Issue:
53(5)
Published: April 2, 2024
Chronic
neuroinflammation
serves
a
key
role
in
the
onset
and
progression
of
neurodegenerative
disorders.
Mitochondria
serve
as
central
regulators
neuroinflammation.
In
addition
to
providing
energy
cells,
mitochondria
also
participate
immunoinflammatory
response
disorders
including
Alzheimer's
disease,
Parkinson's
multiple
sclerosis
epilepsy,
by
regulating
processes
such
cell
death
inflammasome
activation.
Under
inflammatory
conditions,
mitochondrial
oxidative
stress,
epigenetics,
dynamics
calcium
homeostasis
imbalance
may
underlying
regulatory
mechanisms
for
these
diseases.
Therefore,
investigating
related
dysfunction
result
therapeutic
strategies
against
chronic
neurodegeneration.
The
present
review
summarizes
neuroinflammatory
diseases
current
treatment
approaches
that
target
