bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Sept. 3, 2024
The
accumulation
of
alpha-synuclein
(aS)
protein
aggregates
in
cells
is
a
typical
hallmark
several
neurodegenerative
diseases.
Recent
studies
have
shown
that
the
aberrant
transition
monomeric
aS
into
solid-like
can
occur
via
an
intermediate
liquid-like
state,
where
partitions
between
dense
and
dilute
phases.
Although
not
typically
recognized
as
RNA-binding
protein,
it
bind
RNA
under
aggregation
conditions.
However,
impact
on
dynamics
within
phases
remains
unclear.
Here,
we
employ
combination
fluorescence
spectroscopy
techniques
to
explore
both
presence
RNA.
Our
sensitive
analysis
phase
revealed
formation
precursor
nanoclusters
involved
initiating
separation.
We
also
uncovered
heterogeneity
phase,
discovering
molecules
exist
two
distinct
mobility
states:
freely
diffusing
or
confined
micro-domains.
Additionally,
was
found
induce
morphological
changes
phase.
quantitative
analysis,
based
lifetime
measurements,
showed
alters
properties
promoting
liquid-to-solid
transition.
These
findings
indicate
active
role
modulating
material
influencing
its
transitions.
Biomacromolecules,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 26, 2025
This
study
proposes
fluorenylmethoxycarbonyl
(Fmoc)-protected
single
amino
acids
(Fmoc-AAs)
as
a
minimalistic
model
system
to
investigate
liquid-liquid
phase
separation
(LLPS)
and
the
elusive
liquid-to-solid
transition
of
condensates.
We
demonstrated
that
Fmoc-AAs
exhibit
LLPS
depending
on
pH
ionic
strength,
primarily
driven
by
hydrophobic
interactions.
Systematic
examination
conditions
under
which
each
Fmoc-AA
undergoes
revealed
distinct
residue-dependent
trends
in
critical
concentrations
behavior.
Importantly,
we
elucidated
process,
suggesting
it
may
be
molecular
mechanism
different
from
LLPS.
condensates
showed
promise
for
biomolecular
enrichment
catalytic
applications.
work
provides
significant
insights
into
mechanisms
subsequent
transition,
offering
robust
platform
future
studies
related
protocells
protein
aggregation
diseases.
International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(18), P. 10187 - 10187
Published: Sept. 23, 2024
Neurodegenerative
diseases
are
the
leading
cause
of
human
disability
and
immensely
reduce
patients’
life
span
quality.
The
characterized
by
functional
loss
neuronal
cells
share
several
common
pathogenic
mechanisms
involving
malfunction,
structural
distortion,
or
aggregation
multiple
key
regulatory
proteins.
Cellular
phase
separation
is
formation
biomolecular
condensates
that
regulate
numerous
biological
processes,
including
development
synaptic
signaling
transduction.
Aberrant
may
protein
a
general
phenomenon
in
patients
suffering
neurodegenerative
diseases.
In
this
review,
we
summarize
pathological
causes
diseases,
Alzheimer’s
disease,
Parkinson’s
Huntington’s
among
others.
We
discuss
regulation
amyloidogenic
proteins
with
an
emphasis
their
aberrant
aggregation.
also
introduce
approaches
as
potential
therapeutic
strategies
to
ameliorate
through
intervening
Overall,
review
consolidates
research
findings
caused
misfolded
context
The Journal of Cell Biology,
Journal Year:
2024,
Volume and Issue:
223(10)
Published: July 9, 2024
Synaptotagmin-1
(Syt1)
is
a
calcium
sensor
that
regulates
synaptic
vesicle
fusion
in
synchronous
neurotransmitter
release.
Syt1
interacts
with
negatively
charged
lipids
and
the
SNARE
complex
to
control
event.
However,
it
remains
incompletely
understood
how
mediates
Ca2+-trigged
fusion.
Here,
we
discovered
undergoes
liquid-liquid
phase
separation
(LLPS)
form
condensates
both
vitro
living
cells.
play
role
attachment
PM
efficiently
recruit
SNAREs
complexin,
which
may
facilitate
downstream
We
observed
undergo
liquid-to-gel-like
transition,
reflecting
formation
of
oligomers.
The
transition
can
be
blocked
or
reversed
by
Ca2+,
confirming
essential
Ca2+
oligomer
disassembly.
Finally,
showed
mutations
causing
Syt1-associated
neurodevelopmental
disorder
impair
Ca2+-driven
transition.
These
findings
reveal
LLPS
Ca2+-sensitive
providing
new
insights
into
Syt1-mediated
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 29, 2025
Summary
Efforts
to
achieve
precise
and
efficient
tumor
targeting
of
highly
malignant
brain
tumors
are
constrained
by
the
dearth
appropriate
models
study
effects
potential
side
radiation,
chemotherapy,
immunotherapy
on
most
complex
human
organ,
brain.
We
established
a
cerebral
organoid
model
tumorigenesis
in
an
autologous
setting
overexpressing
c-MYC
as
one
common
oncogenes
tumors.
GFP
+
/c-MYC
high
cells
were
isolated
from
organoids
used
two
different
culture
approaches:
assembloids
comprising
normal
with
sphere
co-culture
slices
at
air-liquid
interface
cells.
both
approaches
exhibited
tumor-like
properties,
including
overexpression
oncogene,
proliferative
invasive
potential,
immature
phenotype
evidenced
increased
expression
Ki-67,
VIM,
CD133.
Organoids
served
suitable
scaffolds
for
infiltrating
Using
our
reproducible
powerful
system
that
allows
long-term
culture,
we
demonstrated
migratory
infiltrative
is
shaped
environment
which
glia
provide
support
medRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 13, 2025
Mutations
and
multiplications
in
the
SNCA
gene
,
encoding
alpha-synuclein
(aSyn),
are
associated
with
familial
forms
of
Parkinson's
disease
(PD).
We
report
identification
a
novel
missense
mutation
(NM_000345.4,
cDNA
174G>C;
protein
K58N)
PD
patient
using
whole
exome
sequencing,
describe
comprehensive
molecular
cellular
analysss
effects
this
mutation.
The
exhibited
typical
sporadic
early
onset
benign
course.
Biophysical
studies
revealed
that
K58N
substitution
causes
local
structural
effects,
disrupts
binding
to
membranes,
enhances
aSyn
vitro
aggregation.
produces
fewer
inclusions
per
cell,
fails
undergo
condensate
formation.
increases
cytoplasmic
distribution
protein,
has
minimal
effect
on
dynamic
reversibility
serine-129
phosphorylation.
In
total,
advances
our
understanding
biology
pathobiology.
Cell Reports,
Journal Year:
2025,
Volume and Issue:
44(5), P. 115636 - 115636
Published: May 1, 2025
Alpha-synuclein
(αSyn)
is
an
intrinsically
disordered
protein
that
accumulates
in
the
brains
of
patients
with
Parkinson's
disease
(PD).
Through
a
high-throughput
screen,
we
recently
identified
38
genes
whose
knockdown
modulates
αSyn
propagation.
Here,
show
that,
among
those,
TAX1BP1
regulates
how
interacts
lipids,
and
ADAMTS19
phase
separates
into
inclusions,
adding
to
growing
body
evidence
implicating
those
processes
PD.
RNA
sequencing,
identify
several
are
differentially
expressed
after
or
carry
increased
frequency
rare
risk
variants
PD
versus
healthy
controls.
Those
cluster
within
modules
regions
brain
develop
high
degrees
pathology.
We
propose
model
for
genetic
architecture
sporadic
PD:
burden
across
networks
dysregulates
pathways
underlying
homeostasis
leads
pathology
neurodegeneration.