Chemical Reviews,
Год журнала:
2019,
Номер
119(12), С. 6956 - 6993
Опубликована: Апрель 11, 2019
Amyloids,
fibrillar
assembly
of
(poly)peptide
chains,
are
associated
with
neurodegenerative
illnesses
such
as
Alzheimer's
and
Parkinson's
diseases,
for
which
there
no
cures.
The
molecular
mechanisms
the
formation
toxic
species
still
elusive.
Some
peptides
proteins
can
form
functional
amyloid-like
aggregates
mainly
in
bacteria
fungi
but
also
humans.
Little
is
known
on
differences
self-assembly
pathogenic
(poly)peptides.
We
review
atomistic
coarse-grained
simulation
studies
amyloid
their
monomeric,
oligomeric,
states.
Particular
emphasis
given
to
challenges
one
faces
characterize
at
atomic
level
detail
conformational
space
disordered
(poly)peptides
aggregation.
discuss
difficulties
comparing
results
experimental
data,
we
propose
new
shed
light
aggregation
processes
diseases.
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 Society Reviews,
Год журнала:
2020,
Номер
49(15), С. 5473 - 5509
Опубликована: Янв. 1, 2020
Amyloid
diseases
are
global
epidemics
with
profound
health,
social
and
economic
implications
yet
remain
without
a
cure.
This
dire
situation
calls
for
research
into
the
origin
pathological
manifestations
of
amyloidosis
to
stimulate
continued
development
new
therapeutics.
In
basic
science
engineering,
cross-β
architecture
has
been
constant
thread
underlying
structural
characteristics
functional
amyloids,
realizing
that
amyloid
structures
can
be
both
in
nature
fuelled
innovations
artificial
whose
use
today
ranges
from
water
purification
3D
printing.
At
conclusion
half
century
since
Eanes
Glenner's
seminal
study
amyloids
humans,
this
review
commemorates
occasion
by
documenting
major
milestones
date,
perspectives
biology,
biophysics,
medicine,
microbiology,
engineering
nanotechnology.
We
also
discuss
challenges
opportunities
drive
interdisciplinary
field
moving
forward.
Assembly
of
microtubule-associated
protein
tau
into
filamentous
inclusions
underlies
a
range
neurodegenerative
diseases.
Tau
filaments
adopt
different
conformations
in
Alzheimer’s
and
Pick’s
Here,
we
used
cryo-
immuno-
electron
microscopy
to
characterise
that
were
assembled
from
recombinant
full-length
human
with
four
(2N4R)
or
three
(2N3R)
microtubule-binding
repeats
the
presence
heparin.
2N4R
assembles
multiple
types
filaments,
structures
reveal
similar
‘kinked
hairpin’
folds,
which
second
third
pack
against
each
other.
2N3R
are
structurally
homogeneous,
dimeric
core,
where
two
molecules
parallel
manner.
The
heparin-induced
differ
those
disease,
have
larger
cores
repeat
compositions.
Our
results
illustrate
structural
versatility
amyloid
raise
questions
about
relevance
vitro
assembly.
Molecular Neurodegeneration,
Год журнала:
2019,
Номер
14(1)
Опубликована: Июль 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.
