International Journal of Biological Macromolecules,
Journal Year:
2021,
Volume and Issue:
181, P. 582 - 604
Published: March 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.
FEBS Journal,
Journal Year:
2021,
Volume and Issue:
290(3), P. 554 - 583
Published: Dec. 4, 2021
Disrupted
protein
folding
or
decreased
stability
can
lead
to
the
accumulation
of
(partially)
un-
misfolded
proteins,
which
ultimately
cause
formation
aggregates.
Much
interest
in
aggregation
is
associated
with
its
involvement
a
wide
range
human
diseases
and
challenges
it
poses
for
large-scale
biopharmaceutical
manufacturing
formulation
therapeutic
proteins
peptides.
On
other
hand,
aggregates
also
be
functional,
as
observed
nature,
triggered
use
development
biomaterials
therapeutics
well
improvement
food
characteristics.
Thus,
unmasking
various
steps
involved
critical
obtain
better
understanding
underlying
mechanism
amyloid
formation.
This
knowledge
will
allow
more
tailored
diagnostic
methods
treatments
amyloid-associated
diseases,
applications
fields
new
(bio)materials,
technology
therapeutics.
However,
complex
dynamic
nature
process
makes
study
challenging.
To
provide
guidance
on
how
analyse
aggregation,
this
review
we
summarize
most
commonly
investigated
aspects
some
popular
corresponding
methods.
Nature Chemistry,
Journal Year:
2023,
Volume and Issue:
15(10), P. 1340 - 1349
Published: Sept. 25, 2023
The
maturation
of
liquid-like
protein
condensates
into
amyloid
fibrils
has
been
associated
with
several
neurodegenerative
diseases.
However,
the
molecular
mechanisms
underlying
this
liquid-to-solid
transition
have
remained
largely
unclear.
Here
we
analyse
formation
mediated
by
condensation
low-complexity
domain
hnRNPA1,
a
involved
in
amyotrophic
lateral
sclerosis.
We
show
that
phase
separation
and
fibrillization
are
connected
but
distinct
processes
modulated
different
regions
sequence.
By
monitoring
spatial
temporal
evolution
demonstrate
does
not
occur
homogeneously
inside
droplets
is
promoted
at
interface
condensates.
further
coating
surfactant
molecules
inhibits
fibril
formation.
Our
results
reveal
biomolecular
hnRNPA1
promotes
formation,
therefore
suggesting
interfaces
as
potential
novel
therapeutic
target
against
aberrant
amyloids
condensation.
Science Advances,
Journal Year:
2022,
Volume and Issue:
8(48)
Published: Dec. 2, 2022
Biomolecular
condensates
present
in
cells
can
fundamentally
affect
the
aggregation
of
amyloidogenic
proteins
and
play
a
role
regulation
this
process.
While
liquid-liquid
phase
separation
by
themselves
act
as
an
alternative
nucleation
pathway,
interaction
partly
disordered
aggregation-prone
with
preexisting
that
localization
centers
could
be
far
more
general
mechanism
altering
their
behavior.
Here,
we
show
so-called
host
biomolecular
both
accelerate
slow
down
amyloid
formation.
We
study
protein
α-synuclein
two
truncated
variants
presence
three
types
composed
nonaggregating
peptides,
RNA,
or
ATP.
Our
results
demonstrate
markedly
speed
up
formation
when
localize
to
interface.
However,
also
significantly
suppress
sequestering
stabilizing
proteins,
thereby
providing
living
possible
protection
against
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.
Molecular Neurodegeneration,
Journal Year:
2024,
Volume and Issue:
19(1)
Published: Feb. 20, 2024
The
conversion
of
native
peptides
and
proteins
into
amyloid
aggregates
is
a
hallmark
over
50
human
disorders,
including
Alzheimer's
Parkinson's
diseases.
Increasing
evidence
implicates
misfolded
protein
oligomers
produced
during
the
formation
process
as
primary
cytotoxic
agents
in
many
these
devastating
conditions.
In
this
review,
we
analyze
processes
by
which
are
formed,
their
structures,
physicochemical
properties,
population
dynamics,
mechanisms
cytotoxicity.
We
then
focus
on
drug
discovery
strategies
that
target
ability
to
disrupt
cell
physiology
trigger
degenerative
processes.
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: Feb. 2, 2024
Abstract
Amyloid-β
(Aβ)
oligomers
are
implicated
in
the
onset
of
Alzheimer’s
disease
(AD).
Herein,
quinoline-derived
half-curcumin-dioxaborine
(Q-OB)
fluorescent
probe
was
designed
for
detecting
Aβ
by
finely
tailoring
hydrophobicity
biannulate
donor
motifs
donor-π-acceptor
structure.
Q-OB
shows
a
great
sensing
potency
dynamically
monitoring
oligomerization
during
amyloid
fibrillogenesis
vitro.
In
addition,
we
applied
this
strategy
to
fluorometrically
analyze
self-assembly
kinetics
cerebrospinal
fluids
(CSF)
AD
patients.
The
fluorescence
intensity
patients’
CSF
revealed
marked
change
log
(
I
/
0
)
value
0.34
±
0.13
(cognitive
normal),
0.15
0.12
(mild
cognitive
impairment),
and
0.14
0.10
(AD
dementia),
guiding
distinguish
state
continuum
early
diagnosis
AD.
These
studies
demonstrate
potential
our
approach
can
expand
currently
available
preclinical
diagnostic
platform
stages
AD,
aiding
disruption
pathological
progression
development
appropriate
treatment
strategies.
Chemical Society Reviews,
Journal Year:
2024,
Volume and Issue:
53(10), P. 4976 - 5013
Published: Jan. 1, 2024
Protein
misfolding
and
amyloid
aggregation,
linked
to
neurodegenerative
diseases,
can
result
from
liquid–liquid
phase
separation
(LLPS)
a
subsequent
liquid-to-solid
transition.
This
represents
LLPS
as
generic
mechanism
in
nucleation.
