Nature Communications,
Год журнала:
2020,
Номер
11(1)
Опубликована: Июнь 15, 2020
Abstract
Formation
of
amyloid-beta
(Aβ)
oligomer
pores
in
the
membrane
neurons
has
been
proposed
to
explain
neurotoxicity
Alzheimerʼs
disease
(AD).
Here,
we
present
three-dimensional
structure
an
Aβ
formed
a
mimicking
environment,
namely
Aβ(1-42)
tetramer,
which
comprises
six
stranded
β-sheet
core.
The
two
faces
core
are
hydrophobic
and
surrounded
by
membrane-mimicking
environment
while
edges
hydrophilic
solvent-exposed.
By
increasing
concentration
sample,
octamers
also
formed,
made
tetramers
facing
each
other
forming
β-sandwich
structure.
Notably,
inserted
into
lipid
bilayers
as
well-defined
pores.
To
establish
structure-membrane
activity
relationships,
molecular
dynamics
simulations
were
carried
out.
These
studies
revealed
mechanism
disruption
water
permeation
occurred
through
lipid-stabilized
mediated
residues
located
on
β-sheets
oligomers.
Nature Communications,
Год журнала:
2018,
Номер
9(1)
Опубликована: Авг. 31, 2018
α-Synuclein
(aSyn)
fibrillar
polymorphs
have
distinct
in
vitro
and
vivo
seeding
activities,
contributing
differently
to
synucleinopathies.
Despite
numerous
prior
attempts,
how
polymorphic
aSyn
fibrils
differ
atomic
structure
remains
elusive.
Here,
we
present
fibril
from
the
full-length
recombinant
human
their
capacity
cytotoxicity
vitro.
By
cryo-electron
microscopy
helical
reconstruction,
determine
structures
of
two
predominant
species,
a
rod
twister,
both
at
3.7
Å
resolution.
Our
models
reveal
that
share
kernel
bent
β-arch,
but
inter-protofilament
interfaces.
Thus,
different
packing
same
gives
rise
polymorphs.
Analyses
disease-related
familial
mutations
suggest
potential
contribution
pathogenesis
synucleinopathies
by
altering
population
distribution
Drug
design
targeting
amyloid
neurodegenerative
diseases
should
consider
formation
concurrent
Chemical Reviews,
Год журнала:
2021,
Номер
121(4), С. 2545 - 2647
Опубликована: Фев. 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.
Parkinson’s
disease
is
a
progressive
neuropathological
disorder
that
belongs
to
the
class
of
synucleinopathies,
in
which
protein
alpha-synuclein
found
at
abnormally
high
concentrations
affected
neurons.
Its
hallmark
are
intracellular
inclusions
called
Lewy
bodies
and
neurites.
We
here
report
structure
cytotoxic
fibrils
(residues
1–121),
determined
by
cryo-electron
microscopy
resolution
3.4
Å.
Two
protofilaments
form
polar
fibril
composed
staggered
β-strands.
The
backbone
residues
38
95,
including
core
non-amyloid
component
region,
well
resolved
EM
map.
Residues
50–57,
containing
three
mutation
sites
associated
with
familial
interface
between
two
contribute
stability.
A
hydrophobic
cleft
one
end
may
have
implications
for
elongation,
invites
design
molecules
diagnosis
treatment
synucleinopathies.
Chemical Reviews,
Год журнала:
2019,
Номер
120(6), С. 3210 - 3229
Опубликована: Дек. 5, 2019
Vaccines
have
had
a
profound
impact
on
the
management
and
prevention
of
infectious
disease.
In
addition,
development
vaccines
against
chronic
diseases
has
attracted
considerable
interest
as
an
approach
to
prevent,
rather
than
treat,
conditions
such
cancer,
Alzheimer's
disease,
others.
Subunit
consist
nongenetic
components
agent
or
disease-related
epitope.
this
Review,
we
discuss
peptide-based
their
potential
in
three
therapeutic
areas:
cancer.
We
factors
that
contribute
vaccine
efficacy
how
these
parameters
may
potentially
be
modulated
by
design.
examine
both
clinically
tested
well
nascent
approaches
explore
current
challenges
remedies.
While
peptide
hold
substantial
promise
human
many
obstacles
remain
hampered
clinical
use;
thus,
continued
research
efforts
address
are
warranted.
Nature Communications,
Год журнала:
2019,
Номер
10(1)
Опубликована: Окт. 29, 2019
Abstract
The
formation
of
Aβ
amyloid
fibrils
is
a
neuropathological
hallmark
Alzheimer’s
disease
and
cerebral
angiopathy.
However,
the
structure
from
brain
tissue
poorly
understood.
Here
we
report
purification
meningeal
their
structural
analysis
with
cryo-electron
microscopy.
We
show
that
these
are
polymorphic
but
consist
similarly
structured
protofilaments.
Brain
derived
right-hand
twisted
peptide
fold
differs
sharply
previously
analyzed
were
formed
in
vitro.
These
data
underscore
importance
to
use
patient-derived
when
investigating
basis
disease.
