Abstract
Substantial
advances
in
technology
are
permitting
a
high
resolution
understanding
of
the
salience
glia,
and
have
helped
us
to
transcend
decades
predominantly
neuron‐centric
research.
In
particular,
recent
‘omic’
technologies
enabled
unique
insights
into
glial
biology,
shedding
light
on
cellular
molecular
aspects
neurodegenerative
diseases,
including
amyotrophic
lateral
sclerosis
(ALS).
Here,
we
review
studies
using
omic
techniques
attempt
understand
role
glia
ALS
across
different
model
systems
post
mortem
tissue.
We
also
address
caveats
that
should
be
considered
when
interpreting
such
studies,
how
some
these
may
mitigated
through
either
multi‐omic
approach
and/or
careful
low
throughput,
fidelity
orthogonal
validation
with
particular
emphasis
functional
validation.
Finally,
consider
emerging
their
potential
relevance
deepening
our
ALS.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Май 16, 2024
TAR
DNA-binding
protein
43
(TDP-43)
proteinopathy
in
brain
cells
is
the
hallmark
of
amyotrophic
lateral
sclerosis
(ALS)
but
its
cause
remains
elusive.
Asparaginase-like-1
(ASRGL1)
cleaves
isoaspartates,
which
alter
folding
and
susceptibility
to
proteolysis.
ASRGL1
gene
harbors
a
copy
human
endogenous
retrovirus
HML-2,
whose
overexpression
contributes
ALS
pathogenesis.
Here
we
show
that
expression
was
diminished
samples
by
RNA
sequencing,
immunohistochemistry,
western
blotting.
TDP-43
colocalized
neurons
but,
absence
ASRGL1,
aggregated
cytoplasm.
found
be
prone
isoaspartate
formation
substrate
for
ASRGL1.
silencing
triggered
accumulation
misfolded,
fragmented,
phosphorylated
mislocalized
cultured
motor
cortex
female
mice.
Overexpression
restored
neuronal
viability.
HML-2
led
silencing.
Loss
leading
aggregation
may
critical
mechanism
pathophysiology.
Communications Biology,
Год журнала:
2025,
Номер
8(1)
Опубликована: Фев. 7, 2025
Age-related
long-term
disability
is
attracting
increasing
attention
due
to
the
growing
ageing
population
worldwide.
However,
current
understanding
of
senescent
spinal
cord
remains
insufficient.
Bulk
RNA
sequencing
reveals
that
526
genes
are
upregulated
and
300
downregulated
in
cords.
Pathway
enrichment
analysis
differentially
expressed
shows
senescence
cords
related
phagosome
function,
neuroinflammation,
ferroptosis,
necroptosis.
Prediction
upstream
transcription
factors
interactome
identify
Spi1
as
a
factor
potentially
plays
core
role
Spatial
transcriptomics
illustrates
spatial
distribution
transcriptomic
landscape
both
young
identifies
distinct
neuronal
glial
subtypes.
The
ferroptosis-associated
gene
Fth1
aged
Flow
cytometry
increased
accumulation
free
Fe2+
ROS
mixed
cells;
however,
CCK-8
assays
reveal
these
cells
resistant
ferroptosis.
SiRNA
lentivirus
experiments
indicate
overexpression
normal
reduces
their
sensitivity
whereas
knockdown
increases
In
summary,
bulk
elucidate
transcriptional
characteristics
versus
cords,
thus
highlighting
mediating
ferroptosis
resistance
cells.
Multiomics
sheds
light
on
expression
signature
during
process-resistance
via
upregulation
Fth1.
Amyotrophic
lateral
sclerosis
(ALS)
is
a
progressive
neurodegenerative
disease
characterized
by
motor
neuron
loss.
Microglia
and
astrocyte-driven
neuroinflammation
prominent
in
ALS,
but
the
cell
state
dynamics
pathways
driving
remain
unclear.
We
performed
single-nucleus
RNA
sequencing
of
ALS
spinal
cords
identified
altered
glial
states,
including
increased
expression
inflammatory
activation
markers.
Many
these
signals
converged
on
inflammation
death
regulator
receptor-interacting
protein
kinase
1
(RIPK1)
necroptotic
pathway.
In
superoxide
dismutase
(SOD1)G93A
mice,
blocking
RIPK1
activity
delayed
symptom
onset
impairment
modulated
responses.
used
human
induced
pluripotent
stem
(iPSC)-derived
neuron,
astrocyte,
microglia
tri-cultures
to
identify
potential
biomarkers
that
are
secreted
upon
vitro
inhibition
cerebrospinal
fluid
(CSF)
people
with
ALS.
These
data
reveal
ALS-enriched
populations
associated
suggest
deleterious
role
for
neuroinflammatory
signaling
pathogenesis.
Life Sciences,
Год журнала:
2024,
Номер
354, С. 122952 - 122952
Опубликована: Авг. 9, 2024
The
bidirectional
regulation
between
the
gut
microbiota
and
brain,
known
as
gut-brain
axis,
has
received
significant
attention.
myelin
sheath,
produced
by
oligodendrocytes
or
Schwann
cells,
is
essential
for
efficient
nervous
signal
transmission
maintenance
of
brain
function.
Growing
evidence
shows
that
both
oligodendrogenesis
myelination
are
modulated
its
metabolites,
when
dysbiosis
occurs,
changes
in
composition
and/or
associated
metabolites
may
impact
developmental
occurrence
neurodevelopmental
disabilities.
Although
link
demyelinating
disease
such
multiple
sclerosis
been
extensively
studied,
our
knowledge
about
role
other
myelin-related
disorders,
neurodegenerative
diseases,
limited.
Mechanistically,
microbiota-oligodendrocyte
axis
primarily
mediated
factors
inflammation,
vagus
nerve,
endocrine
hormones,
evidenced
metagenomics,
metabolomics,
vagotomy,
morphological
molecular
approaches.
Treatments
targeting
this
include
probiotics,
prebiotics,
microbial
herbal
bioactive
compounds,
specific
dietary
management.
In
addition
to
commonly
used
approaches,
viral
vector-mediated
tracing
gene
manipulation,
integrated
multiomics
multicenter
clinical
trials
will
greatly
promote
mechanistic
interventional
studies
ultimately,
development
new
preventive
therapeutic
strategies
against
gut-oligodendrocyte
axis-mediated
impairments.
Interestingly,
recent
findings
showed
can
be
induced
hippocampal
damage
reversible
myelin-targeted
drugs,
which
provides
insights
into
understanding
how
hippocampus-based
functional
impairment
(such
Alzheimer's
disease)
regulates
peripheral
homeostasis
systemic
disorders.
