Chemical Society Reviews,
Год журнала:
2021,
Номер
51(2), С. 513 - 565
Опубликована: Дек. 10, 2021
We
discuss
novel
approaches
for
embracing
and
reproducing
complexity
of
Tau
pathology
required
developing
disease-relevant
diagnostics
effective
therapies.
Acta Crystallographica Section D Structural Biology,
Год журнала:
2020,
Номер
76(2), С. 94 - 101
Опубликована: Янв. 30, 2020
Helical
reconstruction
in
RELION
is
increasingly
being
used
to
determine
the
atomic
structures
of
amyloid
filaments
from
electron
cryo-microscopy
(cryo-EM)
images.
However,
because
energy
landscape
refinements
typically
fraught
with
local
optima,
structure
determination
often
difficult.
This
paper
aims
help
users
this
process.
It
discusses
aspects
helical
that
are
particularly
relevant
amyloids,
it
illustrates
problem
optima
refinement
and
how
detect
them,
introduces
a
new
method
calculate
3D
initial
models
reference-free
2D
class
averages.
By
providing
starting
closer
global
optimum,
makes
easier.
All
methods
described
open-source
distributed
within
RELION-3.1.
Their
use
illustrated
using
publicly
available
data
set
on
tau
brain
an
individual
Alzheimer's
disease.
Molecular Neurodegeneration,
Год журнала:
2021,
Номер
16(1)
Опубликована: Дек. 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 Communications,
Год журнала:
2019,
Номер
10(1)
Опубликована: Дек. 4, 2019
Parkinson's
disease
(PD)
and
Multiple
System
Atrophy
(MSA)
are
clinically
distinctive
diseases
that
feature
a
common
neuropathological
hallmark
of
aggregated
α-synuclein.
Little
is
known
about
how
differences
in
α-synuclein
aggregate
structure
affect
phenotype.
Here,
we
amplified
aggregates
from
PD
MSA
brain
extracts
analyzed
the
conformational
properties
using
fluorescent
probes,
NMR
spectroscopy
electron
paramagnetic
resonance.
We
also
generated
several
vitro
polymorphs.
found
brain-derived
fibrils
were
structurally
different
to
all
polymorphs
analyzed.
Importantly,
there
was
greater
structural
heterogeneity
among
compared
those
brain,
possibly
reflecting
on
variability
phenotypes
evident
PD.
Our
findings
have
significant
ramifications
for
use
non-brain-derived
studies,
raise
important
questions
regarding
one
disease-one
strain
hypothesis
study
α-synucleinopathies.
Current Opinion in Structural Biology,
Год журнала:
2019,
Номер
60, С. 7 - 16
Опубликована: Ноя. 3, 2019
In
recent
years
our
understanding
of
amyloid
structure
has
been
revolutionised
by
innovations
in
cryo-electron
microscopy,
electron
diffraction
and
solid-state
NMR.
These
techniques
have
yielded
high-resolution
structures
fibrils
isolated
from
patients
with
neurodegenerative
disease,
as
well
those
formed
amyloidogenic
proteins
vitro.
The
results
not
only
show
the
expected
cross-β
structure,
but
also
reveal
that
fold
is
unexpectedly
diverse
complex.
Here,
we
discuss
this
diversity,
highlighting
dynamic
regions,
ligand
binding
motifs,
cavities,
non-protein
components,
structural
polymorphism.
Collectively,
these
variations
combine
to
allow
generic
be
realised
three
dimensions
different
ways,
diversity
may
related
roles
disease.
Nature Communications,
Год журнала:
2019,
Номер
10(1)
Опубликована: Ноя. 1, 2019
Abstract
ATTR
amyloidosis
is
one
of
the
worldwide
most
abundant
forms
systemic
amyloidosis.
The
disease
caused
by
misfolding
transthyretin
protein
and
formation
amyloid
deposits
at
different
sites
within
body.
Here,
we
present
a
2.97
Å
cryo
electron
microscopy
structure
fibril
purified
from
tissue
patient
with
hereditary
Val30Met
consists
single
protofilament
that
formed
an
N-terminal
C-terminal
fragment
transthyretin.
Our
provides
insights
into
mechanism
implies
early
state
unfolded
molecules,
which
upon
proteolysis
converts
mature
fibrils.
Chemical Reviews,
Год журнала:
2021,
Номер
121(13), С. 8285 - 8307
Опубликована: Июнь 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.