Advanced Science,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 14, 2025
α-Syn
fibrils,
a
key
pathological
hallmark
of
Parkinson's
disease,
is
closely
associated
with
disease
initiation
and
progression.
Several
small
molecules
are
found
to
bind
or
dissolve
α-syn
offering
potential
therapeutic
applications.
Here,
an
innovative
optical
tweezers-based,
fluorescence-combined
approach
developed
probe
the
mechanical
characteristics
fibrils
at
single-molecule
level.
When
subjected
axial
stretching,
local
deformation
within
appeared
forces
above
50
pN.
These
structural
alternations
occurred
stepwise
irreversible,
suggesting
unfolding
individual
subdomains.
Additionally,
exhibits
high
heterogeneity
in
lateral
disruption,
rupture
force
ranging
from
500
The
impact
different
compounds
on
structure
features
further
examined.
Notably,
epigallocatechin
gallate
(EGCG)
generally
attenuates
by
wedging
into
N-terminal
polar
groove
induces
fibril
dissociation.
Conversely,
copper
chlorophyllin
A
(CCA)
attaches
four
sites
wrapping
around
core,
reinforcing
stability
against
forces.
work
offers
effective
method
for
characterizing
single-fibril
properties
bridges
compound-induced
response.
insights
valuable
understanding
amyloid
mechanics
their
regulation
molecules.
Molecular Neurodegeneration,
Год журнала:
2025,
Номер
20(1)
Опубликована: Янв. 23, 2025
Abstract
α-Synucleinopathies
constitute
a
spectrum
of
neurodegenerative
disorders,
including
Parkinson’s
disease
(PD),
Lewy
body
dementia
(LBD),
Multiple
System
Atrophy
(MSA),
and
Alzheimer’s
concurrent
with
LBD
(AD-LBD).
These
disorders
are
unified
by
pathological
hallmark:
aberrant
misfolding
accumulation
α-synuclein
(α-syn).
This
review
delves
into
the
pivotal
role
α-syn,
key
agent
in
α-synucleinopathy
pathophysiology,
provides
survey
potential
therapeutics
that
target
cell-to-cell
spread
pathologic
α-syn.
Recognizing
intricate
complexity
multifactorial
etiology
α-synucleinopathy,
illuminates
various
membrane
receptors,
proteins,
intercellular
spreading
pathways,
agents
for
therapeutic
interventions.
While
significant
progress
has
been
made
understanding
pursuit
efficacious
treatments
remains
challenging.
Several
strategies
involving
decreasing
α-syn
production
aggregation,
increasing
degradation,
lowering
extracellular
inhibiting
cellular
uptake
presented.
The
paper
underscores
necessity
meticulous
comprehensive
investigations
to
advance
our
knowledge
pathology
ultimately
develop
innovative
α-synucleinopathies.
Graphical
Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring,
Год журнала:
2025,
Номер
17(1)
Опубликована: Янв. 1, 2025
Clinicopathological
correlations
differ
by
sex
in
Lewy
body
dementia
(LBD).
However,
previous
studies
have
focused
on
pathological
staging
systems
that
place
less
emphasis
regional
pathologies.
We
included
357
people
(131
female,
226
male)
with
a
high
likelihood
of
LBD
based
pathology
from
the
Brain
Bank
for
Neurodegenerative
(Jacksonville,
FL).
Sex
differences
body,
senile
plaque,
and
neurofibrillary
tangle
counts
their
associations
clinical
diagnosis
were
assessed.
Females
likely
to
diagnosis;
they
had
more
bodies,
tangles,
plaques
various
regions
than
males
(all
p's
<
0.05).
A
higher
was
associated
middle
frontal,
cingulate,
entorhinal
pathology,
so
females
0.045).
clinicopathological
also
occur
at
level.
frequency
misdiagnosis
males.
risk
underdiagnosis
(LBD)
males.Regional
LBD.Regional
association
differs
sex.Regional
stronger
phenotype
Frontiers in Molecular Neuroscience,
Год журнала:
2025,
Номер
18
Опубликована: Фев. 5, 2025
Parkinson’s
disease
(PD)
is
a
progressive
neurodegenerative
disorder
affecting
millions
of
individuals
worldwide.
A
hallmark
PD
pathology
the
accumulation
α-synuclein
(α-Syn),
small
protein
known
to
support
neuronal
development
and
function.
However,
in
PD,
α-Syn
cumulatively
misfolds
into
toxic
aggregates
that
disrupt
cellular
processes
contribute
damage
neurodegeneration.
Previous
studies
implicated
AKT
signaling
pathway
toxicity
models
suggesting
as
potential
therapeutic
target.
Here,
we
investigated
effect
inhibition
Drosophila
model
synucleinopathy.
We
observed
administration
inhibitor,
A-443654
led
mild
improvements
both
survival
motor
function
flies
expressing
human
α-Syn.
Genetic
revealed
reduction
levels
decreased
levels,
concomitant
with
improved
physiological
outcomes.
The
protective
effects
appear
operate
through
fly
ortholog
NF-κB,
Relish,
link
between
NF-κB
regulating
levels.
These
findings
highlight
cascade
target
for
synucleinopathies
provide
insights
mechanisms
could
be
utilized
reduce
related
disorders,
such
multiple
system
atrophy.
Advanced Science,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 14, 2025
α-Syn
fibrils,
a
key
pathological
hallmark
of
Parkinson's
disease,
is
closely
associated
with
disease
initiation
and
progression.
Several
small
molecules
are
found
to
bind
or
dissolve
α-syn
offering
potential
therapeutic
applications.
Here,
an
innovative
optical
tweezers-based,
fluorescence-combined
approach
developed
probe
the
mechanical
characteristics
fibrils
at
single-molecule
level.
When
subjected
axial
stretching,
local
deformation
within
appeared
forces
above
50
pN.
These
structural
alternations
occurred
stepwise
irreversible,
suggesting
unfolding
individual
subdomains.
Additionally,
exhibits
high
heterogeneity
in
lateral
disruption,
rupture
force
ranging
from
500
The
impact
different
compounds
on
structure
features
further
examined.
Notably,
epigallocatechin
gallate
(EGCG)
generally
attenuates
by
wedging
into
N-terminal
polar
groove
induces
fibril
dissociation.
Conversely,
copper
chlorophyllin
A
(CCA)
attaches
four
sites
wrapping
around
core,
reinforcing
stability
against
forces.
work
offers
effective
method
for
characterizing
single-fibril
properties
bridges
compound-induced
response.
insights
valuable
understanding
amyloid
mechanics
their
regulation
molecules.
