bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Aug. 10, 2024
Summary
Human
cerebral
organoids
derived
from
induced
pluripotent
stem
cells
can
recapture
early
developmental
processes
and
reveal
changes
involving
neurodevelopmental
disorders.
Mutations
in
the
X-linked
methyl-CpG
binding
protein
2
(MECP2)
gene
are
associated
with
Rett
syndrome,
disease
severity
varies
depending
on
location
type
of
mutation.
Here,
we
focused
neuronal
activity
syndrome
patient-derived
organoids,
analyzing
two
types
MeCP2
mutations
–
a
missense
mutation
(R306C)
truncating
(V247X)
-
using
calcium
imaging
three-photon
microscopy.
Compared
to
isogenic
controls,
found
abnormal
altered
network
function
based
graph
theoretic
analyses,
V247X
impacting
functional
responses
connectivity
more
severely
than
R306C
mutations.
These
paralleled
EEG
data
obtained
patients
comparable
Labeling
DLX
promoter-driven
inhibitory
neurons
demonstrated
differences
excitatory
Transcriptomic
analyses
revealed
HDAC2-associated
impairment
decreased
GABA
A
receptor
expression
organoids.
findings
demonstrate
mutation-specific
mechanisms
vulnerability
suggest
targeted
strategies
for
their
treatment.
Biomedicines,
Journal Year:
2024,
Volume and Issue:
12(2), P. 457 - 457
Published: Feb. 18, 2024
Multiple
lines
of
evidence
have
shown
that
lactate-mediated
pH
alterations
in
the
brains
patients
with
neuropsychiatric
diseases
such
as
schizophrenia
(SCZ),
Alzheimer’s
disease
(AD)
and
autism
may
be
attributed
to
mitochondrial
dysfunction
changes
energy
metabolism.
While
neuronal
activity
is
associated
reduction
brain
pH,
astrocytes
are
responsible
for
rebalancing
maintain
equilibrium.
As
lactate
level
main
determinant
activities
impacted
by
due
binding
protons
(H+)
various
types
proteins,
altering
their
structure
function
non-neuronal
cells
brain.
Lactate
could
affect
diverse
epigenetic
modifications,
including
histone
lactylation,
which
linked
acetylation
DNA
methylation.
In
this
review,
we
discuss
importance
homeostasis
normal
function,
role
an
essential
regulatory
molecule
its
contributions
abnormalities
diseases,
shed
light
on
lactate-based
pH-modulating
therapies
targeting
modifications.
conclusion,
attempt
highlight
potentials
challenges
translating
lactate-pH-modulating
clinics
treatment
diseases.
iScience,
Journal Year:
2024,
Volume and Issue:
27(3), P. 109296 - 109296
Published: Feb. 23, 2024
Synaptic
abnormalities
are
a
hallmark
of
several
neurological
diseases,
and
clarification
the
underlying
mechanisms
represents
crucial
step
toward
development
therapeutic
strategies.
Rett
syndrome
(RTT)
is
rare
neurodevelopmental
disorder,
mainly
affecting
females,
caused
by
mutations
in
X-linked
methyl-CpG-binding
protein
2
(
Frontiers in Neuroscience,
Journal Year:
2025,
Volume and Issue:
18
Published: Jan. 8, 2025
Neurodevelopmental
disorders
(NDDs)
affect
4.7%
of
the
global
population
and
are
associated
with
delays
in
brain
development
a
spectrum
impairments
that
can
lead
to
lifelong
disability
even
mortality.
Identification
biomarkers
for
accurate
diagnosis
medications
effective
treatment
lacking,
part
due
historical
use
preclinical
model
systems
do
not
translate
well
clinic
neurological
disorders,
such
as
rodents
heterologous
cell
lines.
Human-induced
pluripotent
stem
cells
(hiPSCs)
promising
vitro
system
modeling
NDDs,
providing
opportunities
understand
mechanisms
driving
NDDs
human
neurons.
Functional
assays,
including
patch
clamping,
multielectrode
array,
imaging-based
popular
tools
employed
hiPSC
disease
models
investigation.
Recent
progress
machine
learning
(ML)
algorithms
also
presents
unprecedented
advance
NDD
research
process.
In
this
review,
we
compare
two-dimensional
three-dimensional
formats
modeling,
discuss
applications
functional
offer
insights
on
incorporating
ML
into
hiPSC-based
drug
screening.
Molecular and Cellular Neuroscience,
Journal Year:
2024,
Volume and Issue:
129, P. 103933 - 103933
Published: April 23, 2024
Astrocytes
are
in
constant
communication
with
neurons
during
the
establishment
and
maturation
of
functional
networks
developing
brain.
release
extracellular
vesicles
(EVs)
containing
microRNA
(miRNA)
cargo
that
regulates
transcript
stability
recipient
cells.
Astrocyte
released
factors
thought
to
be
involved
neurodevelopmental
disorders.
Healthy
astrocytes
partially
rescue
Rett
Syndrome
(RTT)
neuron
function.
EVs
isolated
from
stem
cell
progeny
also
correct
aspects
RTT.
cross
blood-brain
barrier
(BBB)
their
is
found
peripheral
blood
which
may
allow
non-invasive
detection
EV
as
biomarkers
produced
by
healthy
astrocytes.
Here
we
characterize
miRNA
sequence
motifs
human
astrocyte
derived
(ADEVs).
First,
induced
Pluripotent
Stem
Cells
(iPSC)
were
differentiated
into
Neural
Progenitor
(NPCs)
subsequently
using
a
rapid
differentiation
protocol.
iPSC
expressed
specific
markers,
displayed
intracellular
calcium
transients
secreted
ADEVs.
miRNAs
identified
RNA-Seq
on
ADEVs
target
gene
pathway
analysis
detected
brain
immune
related
terms.
The
profile
was
consistent
identity,
included
approximately
80
relatively
depleted
suggestive
passive
loading.
About
120
enriched
motif
discovered
binding
sites
for
RNA
proteins
FUS,
SRSF7
CELF5.
miR-483-5p
most
significantly
This
MECP2
expression
has
been
differentially
samples
RTT
patients.
Our
results
identify
potential
selectively
sorted
implicate
protein
dependent
mechanisms
EMBO Molecular Medicine,
Journal Year:
2024,
Volume and Issue:
16(12), P. 3218 - 3246
Published: Sept. 20, 2024
The
beneficial
effects
of
Neural
Precursor
Cell
(NPC)
transplantation
in
several
neurological
disorders
are
well
established
and
they
generally
mediated
by
the
secretion
immunomodulatory
neurotrophic
molecules.
We
therefore
investigated
whether
Rett
syndrome
(RTT),
that
represents
first
cause
severe
intellectual
disability
girls,
might
benefit
from
NPC-based
therapy.
Using
vitro
co-cultures,
we
demonstrate
that,
sensing
pathological
context,
NPC-secreted
factors
induce
recovery
morphological
synaptic
defects
typical
Mecp2
deficient
neurons.
In
vivo,
prove
intracerebral
NPCs
RTT
mice
significantly
ameliorates
functions.
To
uncover
molecular
mechanisms
underpinning
benefic
effects,
analyzed
transcriptional
profile
cerebellum
transplanted
animals,
disclosing
possible
involvement
Interferon
γ
(IFNγ)
pathway.
Accordingly,
report
capacity
IFNγ
to
rescue
defects,
as
motor
cognitive
alterations
models,
thereby
suggesting
this
pathway
a
potential
therapeutic
target
for
RTT.
Archives of Biochemistry and Biophysics,
Journal Year:
2024,
Volume and Issue:
757, P. 110046 - 110046
Published: May 28, 2024
To
date,
Rett
syndrome
(RTT),
a
genetic
disorder
mainly
caused
by
mutations
in
the
X-linked
MECP2
gene,
is
increasingly
considered
broad-spectrum
pathology,
instead
of
just
neurodevelopmental
disease,
due
to
multitude
peripheral
co-morbidities
and
compromised
metabolic
pathways,
affecting
patients.
The
altered
molecular
processes
include
an
impaired
mitochondrial
function,
perturbed
redox
homeostasis,
chronic
subclinical
inflammation
improper
cholesterol
metabolism.
persistent
inflammatory
condition
was
first
defined
ten
years
ago,
as
previously
unrecognized
feature
RTT,
playing
role
pathology
progress
modulation
phenotypical
severity.
In
light
this,
present
work
aims
at
reviewing
current
knowledge
on
status
immune/inflammatory
functions
well
investigating
emerging
mechanisms
underlying
this
with
special
focus
latest
findings
about
inflammasome
system,
autoimmunity
responses
intestinal
micro-
mycobiota.
On
these
bases,
although
further
research
needed,
future
therapeutic
strategies
able
re-establish
adequate
response
could
represent
potential
approaches
for
RTT