Nucleic Acids Research,
Год журнала:
2023,
Номер
unknown
Опубликована: Дек. 12, 2023
Abstract
Defective
DNA
damage
signalling
and
repair
is
a
hallmark
of
age-related
genetic
neurodegenerative
disease.
One
mechanism
implicated
in
disease
progression
damage-driven
neuroinflammation,
which
largely
mediated
by
tissue-resident
immune
cells,
microglia.
Here,
we
utilise
human
microglia-like
cell
models
persistent
ATM
kinase
deficiency
to
investigate
how
genome
instability
shapes
microglial
function.
We
demonstrate
that
upon
the
cytosolic
sensing
cGAS-STING
axis
drives
chronic
inflammation
robust
chemokine
response,
exemplified
production
CCL5
CXCL10.
Transcriptomic
analyses
revealed
migratory
pathways
were
highly
enriched
IFN-β
treatment
iPSC-derived
microglia,
indicating
response
mirrors
type
I
interferon
signalling.
Furthermore,
find
STING
deletion
leads
defect
chemotaxis
under
basal
conditions
loss.
Overall,
this
work
provides
mechanistic
insights
into
cGAS-STING-dependent
neuroinflammatory
mechanisms
consequences
central
nervous
system.
FEBS Journal,
Год журнала:
2018,
Номер
286(6), С. 1058 - 1073
Опубликована: Сен. 21, 2018
The
biology
of
aging
is
an
area
intense
research,
and
many
questions
remain
about
how
why
cell
organismal
functions
decline
over
time.
In
mammalian
cells,
genomic
instability
mitochondrial
dysfunction
are
thought
to
be
among
the
primary
drivers
cellular
aging.
This
review
focuses
on
interrelationship
between
in
cells
its
relevance
age‐related
functional
at
molecular
level.
importance
oxidative
stress
key
DNA
damage
response
pathways
discussed,
with
a
special
focus
poly
(
ADP
‐ribose)
polymerase
1,
whose
persistent
activation
depletes
energy
reserves,
leading
dysfunction,
loss
homeostasis,
altered
metabolism.
Elucidation
relationship
instability,
signaling
that
connect
these
pathways/processes
keys
future
research
human
An
important
component
health
preservation
mitophagy,
this
other
areas
particularly
ripe
for
investigation
will
discussed.
Frontiers in Cell and Developmental Biology,
Год журнала:
2021,
Номер
8
Опубликована: Янв. 7, 2021
Increasing
evidence
suggests
a
strong
interplay
between
autophagy
and
genomic
stability.
Recently,
several
papers
have
demonstrated
molecular
connection
the
DNA
Damage
Response
(DDR)
explored
how
this
link
influences
cell
fate
choice
apoptosis
senescence
in
response
to
different
stimuli.
The
aberrant
deregulation
of
is
linked
development
pathologies,
including
cancer
neurodegeneration.
Ataxia-telangiectasia
mutated
kinase
(ATM)
product
gene
that
lost
Ataxia-Telangiectasia
(A-T),
rare
genetic
disorder
characterized
by
ataxia
cerebellar
neurodegeneration,
defects
immune
response,
higher
incidence
lymphoma
development,
premature
aging.
Importantly,
ATM
plays
central
role
DDR,
it
can
finely
tune
balance
apoptosis:
activated
promotes
particular
sustains
lysosomal-mitochondrial
axis,
which
turn
inhibits
apoptosis.
Therefore,
key
factor
enables
cells
escape
entering
through
modulation
autophagy.
unlike
apoptotic
cells,
senescent
are
viable
ability
secrete
proinflammatory
mitogenic
factors,
thus
influencing
cellular
environment.
In
review
we
aim
summarize
recent
advances
understanding
mechanisms
linking
DDR
senescence,
pointing
out
these
responses.
significance
regulation
pathogenesis
will
be
discussed.
Nucleic Acids Research,
Год журнала:
2023,
Номер
unknown
Опубликована: Дек. 12, 2023
Abstract
Defective
DNA
damage
signalling
and
repair
is
a
hallmark
of
age-related
genetic
neurodegenerative
disease.
One
mechanism
implicated
in
disease
progression
damage-driven
neuroinflammation,
which
largely
mediated
by
tissue-resident
immune
cells,
microglia.
Here,
we
utilise
human
microglia-like
cell
models
persistent
ATM
kinase
deficiency
to
investigate
how
genome
instability
shapes
microglial
function.
We
demonstrate
that
upon
the
cytosolic
sensing
cGAS-STING
axis
drives
chronic
inflammation
robust
chemokine
response,
exemplified
production
CCL5
CXCL10.
Transcriptomic
analyses
revealed
migratory
pathways
were
highly
enriched
IFN-β
treatment
iPSC-derived
microglia,
indicating
response
mirrors
type
I
interferon
signalling.
Furthermore,
find
STING
deletion
leads
defect
chemotaxis
under
basal
conditions
loss.
Overall,
this
work
provides
mechanistic
insights
into
cGAS-STING-dependent
neuroinflammatory
mechanisms
consequences
central
nervous
system.
