Chemical Science,
Journal Year:
2024,
Volume and Issue:
15(7), P. 2528 - 2544
Published: Jan. 1, 2024
Amyloid
fibrils
of
proteins
such
as
α-synuclein
are
a
hallmark
neurodegenerative
diseases
and
much
research
has
focused
on
their
kinetics
mechanisms
formation.
The
question
to
the
thermodynamic
stability
structures
received
less
attention.
Here,
we
newly
utilize
principle
transient
incomplete
separation
species
in
laminar
flow
combination
with
chemical
depolymerization
for
quantification
amyloid
fibril
stability.
relative
concentrations
monomer
at
equilibrium
determined
through
an
Science,
Journal Year:
2022,
Volume and Issue:
375(6577), P. 167 - 172
Published: Jan. 14, 2022
Hi-res
view
of
human
Aβ42
filaments
Alzheimer’s
disease
is
characterized
by
a
loss
memory
and
other
cognitive
functions
the
filamentous
assembly
Aβ
tau
in
brain.
The
peptides
into
that
end
at
residue
42
central
event.
Yang
et
al
.
used
electron
cryo–electron
microscopy
to
determine
structures
from
brain
(see
Perspective
Willem
Fändrich).
They
identified
two
types
related
S-shaped
filaments,
each
consisting
identical
protofilaments.
These
will
inform
development
better
vitro
animal
models,
inhibitors
assembly,
imaging
agents
with
increased
specificity
sensitivity.
—SMH
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.
Nature Medicine,
Journal Year:
2023,
Volume and Issue:
29(6), P. 1448 - 1455
Published: May 29, 2023
Abnormal
α-synuclein
aggregation
is
a
key
pathological
feature
of
group
neurodegenerative
diseases
known
as
synucleinopathies,
which
include
Parkinson's
disease
(PD),
dementia
with
Lewy
bodies
and
multiple
system
atrophy
(MSA).
The
pathogenic
β-sheet
seed
conformation
found
in
various
tissues,
suggesting
potential
biomarker,
but
few
studies
have
been
able
to
reliably
detect
these
seeds
serum
samples.
In
this
study,
we
developed
modified
assay
system,
called
immunoprecipitation-based
real-time
quaking-induced
conversion
(IP/RT-QuIC),
enables
the
detection
individuals
synucleinopathies.
our
internal
first
second
cohorts,
IP/RT-QuIC
showed
high
diagnostic
performance
for
differentiating
PD
versus
controls
(area
under
curve
(AUC):
0.96
(95%
confidence
interval
(CI)
0.95-0.99)/AUC:
0.93
CI
0.84-1.00))
MSA
(AUC:
0.64
0.49-0.79)/AUC:
0.73
0.49-0.98)).
also
0.86
0.74-0.99))
0.80
0.65-0.97))
from
blinded
external
cohort.
Notably,
amplified
maintained
disease-specific
properties,
allowing
differentiation
samples
MSA.
summary,
here
present
novel
platform
that
may
allow
synucleinopathies
using
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.
Nature,
Journal Year:
2023,
Volume and Issue:
625(7993), P. 119 - 125
Published: Nov. 29, 2023
Abstract
Intermediate
species
in
the
assembly
of
amyloid
filaments
are
believed
to
play
a
central
role
neurodegenerative
diseases
and
may
constitute
important
targets
for
therapeutic
intervention
1,2
.
However,
structural
information
about
intermediate
has
been
scarce
molecular
mechanisms
by
which
amyloids
assemble
remain
largely
unknown.
Here
we
use
time-resolved
cryogenic
electron
microscopy
study
vitro
recombinant
truncated
tau
(amino
acid
residues
297–391)
into
paired
helical
Alzheimer’s
disease
or
chronic
traumatic
encephalopathy
3
We
report
formation
shared
first
filament,
with
an
ordered
core
comprising
302–316.
Nuclear
magnetic
resonance
indicates
that
same
adopt
rigid,
β-strand-like
conformations
monomeric
tau.
At
later
time
points,
disappears
observe
many
different
filaments,
structures
depend
on
reaction
conditions.
end
both
reactions,
most
disappear
cores
as
those
from
human
brains
remain.
Our
results
provide
insights
processes
primary
secondary
nucleation
assembly,
implications
design
new
therapies.
