Chemical Society Reviews,
Journal Year:
2021,
Volume and Issue:
51(2), P. 513 - 565
Published: Dec. 10, 2021
We
discuss
novel
approaches
for
embracing
and
reproducing
complexity
of
Tau
pathology
required
developing
disease-relevant
diagnostics
effective
therapies.
Chemical Reviews,
Journal Year:
2021,
Volume and Issue:
121(4), P. 2545 - 2647
Published: Feb. 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.
Nature Communications,
Journal Year:
2019,
Volume and Issue:
10(1)
Published: Oct. 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.
Science,
Journal Year:
2022,
Volume and Issue:
375(6577), P. 167 - 172
Published: Jan. 14, 2022
Hi-res
view
of
human
Aβ42
filaments
Alzheimer’s
disease
is
characterized
by
a
loss
memory
and
other
cognitive
functions
the
filamentous
assembly
Aβ
tau
in
brain.
The
peptides
into
that
end
at
residue
42
central
event.
Yang
et
al
.
used
electron
cryo–electron
microscopy
to
determine
structures
from
brain
(see
Perspective
Willem
Fändrich).
They
identified
two
types
related
S-shaped
filaments,
each
consisting
identical
protofilaments.
These
will
inform
development
better
vitro
animal
models,
inhibitors
assembly,
imaging
agents
with
increased
specificity
sensitivity.
—SMH
Intracellular
inclusions
rich
in
alpha-synuclein
are
a
hallmark
of
several
neuropathological
diseases
including
Parkinson’s
disease
(PD).
Previously,
we
reported
the
structure
fibrils
(residues
1–121),
composed
two
protofibrils
that
connected
via
densely-packed
interface
formed
by
residues
50–57
(Guerrero-Ferreira,
eLife
218;7:e36402).
We
here
report
new
polymorphic
atomic
structures
termed
polymorphs
2a
and
2b,
at
3.0
Å
3.4
resolution,
respectively.
These
show
radically
different
compared
to
previously
polymorphs.
The
have
10
nm
fibril
diameter
protofilaments
which
interact
intermolecular
salt-bridges
between
amino
acids
K45,
E57
(polymorph
2a)
or
E46
2b).
non-amyloid
component
(NAC)
region
is
fully
buried
non-described
interactions
with
N-terminus.
A
hydrophobic
cleft,
location
familial
PD
mutation
sites,
nature
protofilament
now
invite
formulate
hypotheses
about
formation,
growth
stability.