Neurobiology of Disease,
Journal Year:
2020,
Volume and Issue:
146, P. 105086 - 105086
Published: Sept. 22, 2020
Increasing
evidence
suggests
that
alpha-synuclein
(α-syn)
oligomers
are
obligate
intermediates
in
the
pathway
involved
α-syn
fibrillization
and
Lewy
body
(LB)
formation,
may
also
accumulate
within
LBs
Parkinson's
disease
(PD)
other
synucleinopathies.
Therefore,
development
of
tools
methods
to
detect
quantify
has
become
increasingly
crucial
for
mechanistic
studies
understand
their
role
PD,
develop
new
diagnostic
therapies
PD
The
majority
these
rely
primarily
on
use
aggregation
state-specific
or
conformation-specific
antibodies.
Given
impact
data
knowledge
generated
using
antibodies
shaping
foundation
directions
research,
it
is
thoroughly
characterized,
specificity
ability
capture
diverse
species
tested
validated.
Herein,
we
describe
an
antibody
characterization
validation
pipeline
allows
a
systematic
investigation
well-defined
well-characterized
preparations
various
species,
including
monomers,
fibrils,
different
oligomer
characterized
by
distinct
morphological,
chemical
secondary
structure
properties.
This
was
used
characterize
18
antibodies,
16
which
have
been
reported
as
conformation-
oligomer-specific
array
techniques,
immunoblot
analysis
(slot
blot
Western
blot),
digital
ELISA
assay
single
molecule
technology
surface
plasmon
resonance.
Our
results
show
i)
none
specific
one
particular
type
fibrils;
ii)
all
were
be
recognized
fibrillar
α-syn;
iii)
few
showed
high
fibrils
but
did
not
bind
monomers.
These
findings
suggest
great
aggregate-specific
do
differentiate
between
thus
highlighting
importance
exercising
caution
when
interpreting
obtained
underscore
critical
before
therapeutic
agents.
will
only
improve
quality
reproducibility
research
reduce
costs
number
failures
clinic.
Chemical Reviews,
Journal Year:
2021,
Volume and Issue:
121(4), P. 2545 - 2647
Published: Feb. 5, 2021
Protein
misfolding
and
aggregation
is
observed
in
many
amyloidogenic
diseases
affecting
either
the
central
nervous
system
or
a
variety
of
peripheral
tissues.
Structural
dynamic
characterization
all
species
along
pathways
from
monomers
to
fibrils
challenging
by
experimental
computational
means
because
they
involve
intrinsically
disordered
proteins
most
diseases.
Yet
understanding
how
amyloid
become
toxic
challenge
developing
treatment
for
these
Here
we
review
what
computer,
vitro,
vivo,
pharmacological
experiments
tell
us
about
accumulation
deposition
oligomers
(Aβ,
tau),
α-synuclein,
IAPP,
superoxide
dismutase
1
proteins,
which
have
been
mainstream
concept
underlying
Alzheimer's
disease
(AD),
Parkinson's
(PD),
type
II
diabetes
(T2D),
amyotrophic
lateral
sclerosis
(ALS)
research,
respectively,
years.
Molecular Neurodegeneration,
Journal Year:
2019,
Volume and Issue:
14(1)
Published: July 22, 2019
Alpha-synuclein
(αS)
is
the
major
constituent
of
Lewy
bodies
and
a
pathogenic
hallmark
all
synucleinopathathies,
including
Parkinson's
disease
(PD),
dementia
with
(DLB),
multiple
system
atrophy
(MSA).
All
diseases
are
determined
by
αS
aggregate
deposition
but
can
be
separated
into
distinct
pathological
phenotypes
diagnostic
criteria.
Here
we
attempt
to
reinterpret
literature,
particularly
in
terms
how
structure
may
relate
pathology.
We
do
so
context
rapidly
evolving
field,
taking
account
newly
revealed
structural
information
on
both
native
forms
protein,
recent
solid
state
NMR
cryoEM
fibril
structures.
discuss
these
new
findings
impact
current
understanding
PD,
where
this
direct
field.
Molecular Neurodegeneration,
Journal Year:
2021,
Volume and Issue:
16(1)
Published: Dec. 18, 2021
Synucleinopathies
are
clinically
and
pathologically
heterogeneous
disorders
characterized
by
pathologic
aggregates
of
α-synuclein
in
neurons
glia,
the
form
Lewy
bodies,
neurites,
neuronal
cytoplasmic
inclusions,
glial
inclusions.
can
be
divided
into
two
major
disease
entities:
body
multiple
system
atrophy
(MSA).
Common
clinical
presentations
Parkinson's
(PD),
PD
with
dementia,
dementia
bodies
(DLB),
while
MSA
has
subtypes,
predominant
cerebellar
ataxia
parkinsonism.
There
currently
no
disease-modifying
therapies
for
synucleinopathies,
but
information
obtained
from
molecular
genetics
models
that
explore
mechanisms
conversion
to
oligomers
insoluble
fibrils
offer
hope
eventual
therapies.
It
remains
unclear
how
associated
distinct
cellular
pathologies
(e.g.,
inclusions)
what
factors
determine
neuroanatomical
cell
type
vulnerability.
Accumulating
evidence
vitro
vivo
experiments
suggests
species
derived
"strains"
having
different
seeding
properties.
Recent
advancements
assays,
such
as
real-time
quaking-induced
(RT-QuIC)
protein
misfolding
cyclic
amplification
(PMCA),
not
only
demonstrate
activity
also
exciting
opportunities
diagnosis
using
readily
accessible
peripheral
tissue
samples.
Cryogenic
electron
microscopy
(cryo-EM)
structural
studies
recombinant
or
brain-derived
filaments
provide
new
insight
synucleinopathies.
In
this
review,
we
describe
clinical,
genetic
neuropathologic
features
including
a
discussion
evolution
classification
staging
disease.
We
brief
on
proposed
formation,
well
supporting
existence
strains
MSA.
Abundant
filamentous
inclusions
of
tau
are
characteristic
more
than
20
neurodegenerative
diseases
that
collectively
termed
tauopathies.
Electron
cryo-microscopy
(cryo-EM)
structures
amyloid
filaments
from
human
brain
revealed
distinct
folds
characterise
many
different
diseases.
A
lack
laboratory-based
model
systems
to
generate
these
has
hampered
efforts
uncover
the
molecular
mechanisms
underlie
Here,
we
report
in
vitro
assembly
conditions
with
recombinant
replicate
both
Alzheimer's
disease
(AD)
and
chronic
traumatic
encephalopathy
(CTE),
as
determined
by
cryo-EM.
Our
results
suggest
post-translational
modifications
modulate
filament
assembly,
previously
observed
additional
densities
AD
CTE
may
arise
presence
inorganic
salts,
like
phosphates
sodium
chloride.
In
into
disease-relevant
will
facilitate
studies
determine
their
roles
diseases,
well
development
compounds
specifically
bind
or
prevent
formation.
Brain,
Journal Year:
2022,
Volume and Issue:
145(9), P. 3058 - 3071
Published: March 25, 2022
Abstract
To
date,
no
reliable
clinically
applicable
biomarker
has
been
established
for
Parkinson’s
disease.
Our
results
indicate
that
a
long
anticipated
blood
test
disease
may
be
realized.
Following
the
isolation
of
neuron-derived
extracellular
vesicles
patients
and
non-Parkinson’s
individuals,
immunoblot
analyses
were
performed
to
detect
vesicle-derived
α-synuclein.
Pathological
α-synuclein
forms
derived
from
neuronal
could
detected
under
native
conditions
significantly
increased
in
all
individuals
with
clearly
distinguished
non-disease
state.
By
performing
an
seeding
assay
these
soluble
conformers
amplified
pathological
protein
folding
was
demonstrated.
Amplified
exhibited
β-sheet-rich
structures
fibrillary
appearance.
study
demonstrates
detection
plasma
samples
potential
evolve
into
blood-biomarker
is
still
lacking
so
far.
Moreover,
distribution
seeding-competent
within
exosomes
sheds
new
light
mechanisms
neurodegenerative
disorders.
Chemical Reviews,
Journal Year:
2021,
Volume and Issue:
121(13), P. 8285 - 8307
Published: June 17, 2021
This
review
will
focus
on
the
process
of
amyloid-type
protein
aggregation.
Amyloid
fibrils
are
an
important
hallmark
misfolding
diseases
and
therefore
have
been
investigated
for
decades.
Only
recently,
however,
atomic
or
near-atomic
resolution
structures
elucidated
from
various
in
vitro
ex
vivo
obtained
fibrils.
In
parallel,
fibril
formation
has
studied
under
highly
artificial
but
comparatively
reproducible
conditions.
The
starts
with
a
summary
what
is
known
speculated
aggregation
experiments.
A
partially
hypothetic
selection
model
be
described
that
may
suitable
to
explain
why
amyloid
look
way
they
do,
particular,
at
least
all
so
far
reported
high
cryo-electron
microscopy
register,
cross-β-sheet
mostly
consist
two
protofilaments
twisted
around
each
other.
An
intrinsic
feature
prion-like
nature
assemblies.
Transferring
point
view
situation
not
straightforward,
hypothetic,
leaves
many
open
questions
need
addressed
future.