Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials
Cells,
Год журнала:
2024,
Номер
13(5), С. 452 - 452
Опубликована: Март 5, 2024
Despite
tremendous
efforts
in
basic
research
and
a
growing
number
of
clinical
trials
aiming
to
find
effective
treatments,
amyotrophic
lateral
sclerosis
(ALS)
remains
an
incurable
disease.
One
possible
reason
for
the
lack
causative
treatment
options
is
that
ALS
may
not
be
single
disease
entity
but
rather
represent
syndrome,
with
diverse
genetic
molecular
causes,
histopathological
alterations,
subsequent
presentations
contributing
its
complexity
variability
among
individuals.
Defining
way
subcluster
patients
becoming
central
endeavor
field.
Identifying
specific
clusters
applying
them
could
enable
development
more
treatments.
This
review
aims
summarize
available
data
on
heterogeneity
regard
various
aspects,
e.g.,
clinical,
genetic,
molecular.
Язык: Английский
Metabolomic and Proteomic Profiling of Serum-Derived Extracellular Vesicles from Early-Stage Amyotrophic Lateral Sclerosis Patients
Journal of Molecular Neuroscience,
Год журнала:
2025,
Номер
75(1)
Опубликована: Фев. 15, 2025
Язык: Английский
ALS-linked SOD1 mutations impair mitochondrial-derived vesicle formation and accelerate aging
Redox Biology,
Год журнала:
2023,
Номер
69, С. 102972 - 102972
Опубликована: Ноя. 24, 2023
Oxidative
stress
(OS)
is
regarded
as
the
dominant
theory
for
aging.
While
compelling
correlative
data
have
been
generated
to
support
OS
theory,
a
direct
cause-and-effect
relationship
between
accumulation
of
oxidation-mediated
damage
and
aging
has
not
firmly
established.
Superoxide
dismutase
1
(SOD1)
primary
antioxidant
in
all
cells.
It
is,
however,
susceptible
oxidation
due
gains
toxic
properties
This
study
investigates
role
oxidized
SOD1
derived
from
amyotrophic
lateral
sclerosis
(ALS)
linked
mutations
cell
senescence
Herein,
we
shown
that
line
NSC34
expressing
G93A
mutation
human
(hSOD1G93A)
entered
premature
evidenced
by
decreased
number
5-ethynyl-2′-deoxyuridine
(EdU)-positive
There
was
an
upregulation
cellular
markers
compared
cells
wild-type
(hSOD1WT).
Transgenic
mice
carrying
hSOD1G93A
gene
showed
phenotypes
at
early
age
(135
days)
with
high
levels
P53
P16
but
low
SIRT1
SIRT6
age-matched
hSOD1WT
transgenic
mice.
Notably,
were
significantly
elevated
both
senescent
135-day
Selective
removal
our
CT4-directed
autophagy
decelerated
aging,
indicating
causal
factor
Intriguingly,
mitochondria
malfunctioned
middle-aged
hSODG93A
They
exhibited
increased
production
mitochondrial-derived
vesicles
(MDVs)
response
mild
mutant
hSOD1
younger
age;
mitochondrial
gradually
declined
In
conclusion,
show
ALS-linked
mutants
Compromised
responsiveness
may
serve
indicator
Язык: Английский
Role of Retroelements in Frontotemporal Dementia Development
Frontiers in Bioscience-Scholar,
Год журнала:
2025,
Номер
17(1)
Опубликована: Янв. 22, 2025
Frontotemporal
dementia
(FTD)
develops
in
proteinopathies
involving
TDP-43
(transactive
response
DNA-binding
protein
43
kDa),
tau,
and
FUS
(fused
sarcoma)
proteins,
which
possess
antiviral
properties
exert
inhibitory
effects
on
human
transposable
elements.
Viruses
aging
have
been
suggested
to
trigger
FTD
by
activating
specific
retroelements.
is
associated
with
multiple
single
nucleotide
polymorphisms
(SNPs),
most
located
intergenic
regulatory
regions
where
many
element
genes
are
found.
Therefore,
genetic
predisposition
may
influence
the
interaction
between
retroelements
TDP-43,
causing
pathological
conformation
changes
aggregate
formation.
Subsequently,
these
aggregates
lose
their
ability
inhibit
retroelements,
leading
activation
of
This
creates
a
harmful
negative
feedback
loop
expressions
further
enhanced
retroelement
transcripts
resulting
accumulation
disease
progression.
Hence,
epigenetic
inhibition
pathologically
activated
using
micro-ribonucleic
acids
(microRNAs)
derived
from
elements
has
proposed
as
potential
treatment
for
FTD.
Finally,
review
current
scientific
literature
identified
13
appropriate
microRNAs
(miR-1246,
-181c,
-330,
-345-5p,
-361,
-548a-3p,
-548b-5p,
-548c-5p,
-571,
-588,
-659-3p,
-708-3p,
-887).
Язык: Английский
Extracellular Vesicles from NSC-34 MN-like Cells Transfected with Mutant SOD1 Modulate Inflammatory Status of Raw 264.7 Macrophages
Genes,
Год журнала:
2024,
Номер
15(6), С. 735 - 735
Опубликована: Июнь 3, 2024
Amyotrophic
lateral
sclerosis
(ALS)
is
a
neurodegenerative
disease
targeting
the
brain
and
spinal
cord.
Non-neuronal
cells,
including
macrophages,
may
contribute
to
disruption
of
motor
neurons
(MNs),
neuromuscular
junction
dismantling
clinical
signs
ALS.
Understanding
modality
effect
MNs–macrophage
communication
pivotal.
Here,
we
focus
on
extracellular
vesicle
(EVS)-mediated
and,
in
particular,
analyze
response
macrophages.
NSC-34
cells
transfected
with
mutant
SOD1
(G93A,
A4V,
G85R,
G37R)
differentiated
towards
MN-like
Raw
264.7
macrophages
are
cellular
models
study.
mSOD1
release
high
number
vesicles,
both
large-lEVs
(300
nm
diameter)
small-sEVs
(90
diameter),
containing
inflammation-modulating
molecules,
efficiently
taken
up
by
RT-PCR
analysis
inflammation
mediators
demonstrated
that
conditioned
medium
polarizes
pro-inflammatory
anti-inflammatory
phenotypes.
sEVs
act
time-dependent
manner:
an
mediated
TGFβ
firstly
starts
(12
h);
successively,
shifts
pro-inflammation
IL-1β-mediated
(48
h).
The
strictly
dependent
mutation
type.
results
suggest
EVs
impact
physiological
behavioral
macrophage
processes
potential
relevance
MN
degeneration.
Язык: Английский
Aberrant evoked calcium signaling and nAChR cluster morphology in a SOD1 D90A hiPSC-derived neuromuscular model
Frontiers in Cell and Developmental Biology,
Год журнала:
2024,
Номер
12
Опубликована: Июнь 20, 2024
Familial
amyotrophic
lateral
sclerosis
(ALS)
is
a
progressive
neuromuscular
disorder
that
due
to
mutations
in
one
of
several
target
genes,
including
SOD1
.
So
far,
clinical
records,
rodent
studies,
and
vitro
models
have
yielded
arguments
for
either
primary
motor
neuron
disease,
or
pleiotropic
pathogenesis
ALS.
While
mouse
lack
the
human
origin,
using
induced
pluripotent
stem
cells
(hiPSC)
been
recently
developed
addressing
ALS
pathogenesis.
In
spite
improvements
regarding
generation
muscle
from
hiPSC,
degree
maturation
resulting
these
protocols
has
remained
limited.
To
fill
shortcomings,
we
here
present
new
protocol
an
enhanced
myotube
differentiation
hiPSC
with
option
further
upon
coculture
hiPSC-derived
neurons.
The
described
model
first
yield
combination
key
myogenic
features
are
consistent
sarcomeric
organization
association
complex
nAChR
clusters
myotubes
derived
control
hiPSC.
this
model,
carrying
D90A
mutation
had
reduced
expression
markers,
sarcomeres,
morphologically
different
clusters,
altered
nAChR-dependent
Ca
2+
response
compared
myotubes.
Notably,
trophic
support
provided
by
neurons
cluster
differences
between
summary,
novel
yields
evidence
both
muscle-intrinsic
nerve-dependent
aspects
dysfunction
-based
Язык: Английский
Current status and new avenues of stem cell-based preclinical and therapeutic approaches in amyotrophic lateral sclerosis
Expert Opinion on Biological Therapy,
Год журнала:
2024,
Номер
24(9), С. 933 - 954
Опубликована: Авг. 20, 2024
Cell
therapy
development
represents
a
critical
challenge
in
amyotrophic
lateral
sclerosis
(ALS)
research.
Despite
more
than
20
years
of
basic
and
clinical
research,
no
definitive
safety
efficacy
results
cell-based
therapies
for
ALS
have
been
published.
Язык: Английский
Expression Changes of miRNAs in Humans and Animal Models of Amyotrophic Lateral Sclerosis and Their Potential Application for Clinical Diagnosis
Life,
Год журнала:
2024,
Номер
14(9), С. 1125 - 1125
Опубликована: Сен. 6, 2024
Amyotrophic
lateral
sclerosis
(ALS)
is
a
severe
motor
neuron
disease.
Current
detection
methods
can
only
confirm
the
diagnosis
at
onset
of
disease,
missing
critical
window
for
early
treatment.
Recent
studies
using
animal
models
have
found
that
detecting
changes
in
miRNA
sites
predict
and
severity
disease
its
stages,
facilitating
miRNAs
show
expression
neurons
connect
brain,
spinal
cord,
brain
stem,
as
well
skeletal
muscle
mouse
ALS.
Clinically,
some
patients
align
with
those
models,
such
upregulation
miR-29b
miR-206
muscle.
This
study
provides
an
overview
findings
humans
including
SOD1,
FUS,
TDP-43,
C9orf72
transgenic
mice
wobbler
mice,
highlighting
potential
diagnostic
markers
miR-21
are
aberrantly
expressed
both
model
patient
samples,
positioning
them
key
Additionally,
miR-29a,
miR-29b,
miR-181a,
miR-142-3p
shown
aberrant
types
samples
promise
clinical
targets
Finally,
miR-1197
miR-486b-5p
been
recently
identified
ALS,
although
further
needed
to
determine
their
viability
targets.
Язык: Английский
Proteomic Profile of Circulating Extracellular Vesicles in the Brain after Δ9-Tetrahydrocannabinol Inhalation
Biomolecules,
Год журнала:
2024,
Номер
14(9), С. 1143 - 1143
Опубликована: Сен. 10, 2024
Given
the
increasing
use
of
cannabis
in
US,
there
is
an
urgent
need
to
better
understand
drug’s
effects
on
central
signaling
mechanisms.
Extracellular
vesicles
(EVs)
have
been
identified
as
intercellular
mediators
that
contain
a
variety
cargo,
including
proteins.
Here,
we
examined
whether
main
psychoactive
component
cannabis,
Δ9-tetrahydrocannabinol
(THC),
alters
EV
protein
dynamics
brain.
We
first
conducted
vitro
studies,
which
found
THC
activates
choroid
plexus
epithelial
cells,
resulting
transcriptional
upregulation
cannabinoid
1
receptor
and
immediate
early
gene
c-fos,
addition
release
EVs
containing
RNA
cargo.
Next,
male
female
rats
were
for
either
acute
or
chronic
exposure
aerosolized
(‘vaped’)
circulating
brain
EVs.
Cerebrospinal
fluid
was
extracted
from
brain,
isolated
processed
with
label-free
quantitative
proteomic
analyses
via
high-resolution
tandem
mass
spectrometry.
Interestingly,
EV-localized
proteins
differentially
expressed
based
sex-specific
manner.
Taken
together,
these
findings
reveal
acts
modulate
signaling,
thereby
providing
novel
understanding
how
exogenous
factors
can
regulate
communication
Язык: Английский
Intraventricular Administration of Exosomes from Patients with Amyotrophic Lateral Sclerosis Provokes Motor Neuron Disease in Mice
Acta Naturae,
Год журнала:
2024,
Номер
16(4), С. 73 - 80
Опубликована: Дек. 9, 2024
Amyotrophic
lateral
sclerosis
(ALS)
is
a
severe
disease
of
the
central
nervous
system
(CNS)
characterized
by
motor
neuron
damage
leading
to
death
from
respiratory
failure.
The
neurodegenerative
process
in
ALS
an
accumulation
aberrant
proteins
(TDP-43,
SOD1,
etc.)
CNS
cells.
trans-synaptic
transmission
these
via
exosomes
may
be
one
mechanisms
through
which
pathology
progresses.
aim
this
work
was
study
effect
intraventricular
injection
obtained
cerebrospinal
fluid
(CSF)
patients
on
activity
and
pathomorphology
mice.
were
two
healthy
donor.
Exosome
suspensions
at
high
low
concentrations
injected
into
brain
ventricles
male
BALB/c
mice
(n
=
45).
Motor
physiological
parameters
evaluated
twice
month;
morphological
examination
spinal
cord
performed
14
months
after
start
experiment.
Nine
administration
patients,
animals
started
exhibiting
pathological
phenotype;
i.e.,
altered
locomotion
with
paresis
hind
limbs,
coordination
impairment,
increasing
episodes
immobility.
symptoms
accelerated
higher
concentration
exosomes.
experimental
group
showed
significant
decrease
density
ventral
horns
cord,
increase
number
microglial
cells,
microglia
activation.
TDP43
protein
control
localized
nuclei
neurons.
mislocation
its
cytoplasm
observed
group.
Thus,
triggering
exosomal
derived
CSF
development
established.
This
confirms
pathogenetic
role
progression
makes
it
possible
identify
new
target
for
therapy.
Язык: Английский