International Journal of Biological Macromolecules,
Год журнала:
2021,
Номер
181, С. 582 - 604
Опубликована: Март 23, 2021
Many
neurodegenerative
diseases
are
rooted
in
the
activities
of
amyloid-like
proteins
which
possess
conformations
that
spread
to
healthy
proteins.
These
include
Alzheimer's
disease
(AD),
Parkinson's
(PD),
Huntington's
(HD)
and
amyotrophic
lateral
sclerosis
(ALS).
While
their
clinical
manifestations
vary,
protein-level
mechanisms
remarkably
similar.
Aberrant
monomeric
undergo
conformational
shifts,
facilitating
aggregation
formation
solid
fibrils.
However,
there
is
growing
evidence
intermediate
oligomeric
stages
key
drivers
neuronal
toxicity.
Analysis
protein
dynamics
complicated
by
fact
nucleation
growth
not
a
linear
pathway.
Feedback
within
this
pathway
results
exponential
acceleration
aggregation,
but
exerted
oligomers
fibrils
can
alter
cellular
interactions
environment
as
whole.
The
resulting
cascade
effects
likely
contributes
late
onset
accelerating
progression
disorders
widespread
they
have
on
body.
In
review
we
explore
associated
with
AD,
PD,
HD
ALS,
well
common
aggregation.
From
this,
identify
core
elements
pathological
been
targeted
for
therapies,
may
become
future
therapeutic
targets.
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.
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.
Molecules,
Год журнала:
2020,
Номер
25(5), С. 1195 - 1195
Опубликована: Март 6, 2020
The
aggregation
of
a
polypeptide
chain
into
amyloid
fibrils
and
their
accumulation
deposition
insoluble
plaques
intracellular
inclusions
is
the
hallmark
several
misfolding
diseases
known
as
amyloidoses.
Alzheimer's,
Parkinson's
Huntington's
are
some
approximately
50
described
to
date.
identification
characterization
molecular
species
critical
for
formation
disease
development
have
been
focus
intense
scrutiny.
Methods
such
X-ray
electron
diffraction,
solid-state
nuclear
magnetic
resonance
spectroscopy
(ssNMR)
cryo-electron
microscopy
(cryo-EM)
extensively
used
they
contributed
shed
new
light
onto
structure
amyloid,
revealing
multiplicity
polymorphic
structures
that
generally
fit
cross-β
motif.
rational
therapeutic
approaches
against
these
debilitating
increasingly
frequent
requires
thorough
understanding
mechanisms
underlying
cascade.
Here,
we
review
current
knowledge
on
fibril
proteins
peptides
from
kinetic
thermodynamic
point
view,
involved
in
amyloidogenic
process,
origin
cytotoxicity.
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.
Molecular Neurodegeneration,
Год журнала:
2021,
Номер
16(1)
Опубликована: Авг. 28, 2021
Abstract
Alzheimer’s
disease
(AD)
is
pathologically
defined
by
the
presence
of
fibrillar
amyloid
β
(Aβ)
peptide
in
extracellular
senile
plaques
and
tau
filaments
intracellular
neurofibrillary
tangles.
Extensive
research
has
focused
on
understanding
assembly
mechanisms
neurotoxic
effects
Aβ
during
last
decades
but
still
we
only
have
a
brief
associated
biological
processes.
This
review
highlights
many
other
constituents
that,
beside
Aβ,
are
accumulated
plaques,
with
focus
proteins.
All
living
organisms
rely
delicate
network
protein
functionality.
Deposition
significant
amounts
certain
proteins
insoluble
inclusions
will
unquestionably
lead
to
disturbances
network,
which
may
contribute
AD
copathology.
paper
provide
comprehensive
overview
that
been
shown
interact
discussion
their
potential
roles
pathology.
Methods
can
expand
knowledge
about
how
incorporated
described.
Top-down
methods
analyze
post-mortem
tissue
bottom-up
approaches
molecular
insights
organization
plaque-like
particles
compared.
Finally,
analysis
Aβ-interacting
partners
enriched
functional
structural
key
words
presented.
Cold Spring Harbor Perspectives in Biology,
Год журнала:
2019,
Номер
12(2), С. a033878 - a033878
Опубликована: Апрель 1, 2019
Christopher
M.
Dobson,
Tuomas
P.J.
Knowles
and
Michele
Vendruscolo
Centre
for
Misfolding
Diseases,
Department
of
Chemistry,
University
Cambridge,
Cambridge
CB2
1EW,
United
Kingdom
Correspondence:
cmd44{at}cam.ac.uk;
tpjk2{at}cam.ac.uk;
mv245{at}cam.ac.uk
Nature Communications,
Год журнала:
2022,
Номер
13(1)
Опубликована: Дек. 13, 2022
Abstract
Biomolecular
condensates
form
via
coupled
associative
and
segregative
phase
transitions
of
multivalent
macromolecules.
Phase
separation
to
percolation
is
one
example
such
transitions.
Here,
we
characterize
molecular
mesoscale
structural
descriptions
formed
by
intrinsically
disordered
prion-like
low
complexity
domains
(PLCDs).
These
systems
conform
sticker-and-spacers
architectures.
Stickers
are
cohesive
motifs
that
drive
interactions
through
reversible
crosslinking
spacers
affect
the
cooperativity
overall
macromolecular
solubility.
Our
computations
reproduce
experimentally
measured
sequence-specific
behaviors
PLCDs.
Within
simulated
condensates,
networks
inter-sticker
crosslinks
organize
PLCDs
into
small-world
topologies.
The
dimensions
vary
with
spatial
location,
being
most
expanded
at
preferring
be
oriented
perpendicular
interface.
results
demonstrate
even
simple
type
macromolecule
feature
inhomogeneous
organizations
molecules
interfacial
features
likely
prime
them
for
biochemical
activity.
