Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques,
Год журнала:
2022,
Номер
50(3), С. 329 - 345
Опубликована: Март 31, 2022
ABSTRACT:
Neurodegenerative
diseases
are
a
pathologically,
clinically
and
genetically
diverse
group
of
disorders
without
effective
disease-modifying
therapies.
Pathologically,
these
characterised
by
disease-specific
protein
aggregates
in
neurons
and/or
glia
referred
to
as
proteinopathies.
Many
neurodegenerative
show
pathological
overlap
with
the
same
abnormally
deposited
occurring
anatomically
distinct
regions,
which
give
rise
specific
patterns
cognitive
motor
clinical
phenotypes.
Sequential
distribution
inclusions
throughout
brain
have
been
described.
Rather
than
isolation,
it
is
increasingly
recognised
that
combinations
one
or
more
proteinopathies
cerebrovascular
disease
frequently
occur
individuals
diseases.
In
addition,
complex
constellations
ageing-related
incidental
pathologies
associated
tau,
TDP-43,
Aβ,
α-synuclein
deposition
commonly
reported
longitudinal
ageing
studies.
This
review
provides
an
overview
current
classification
age-related
presents
spectrum
complexity
mixed
community-based,
studies,
major
proteinopathies,
genetic
conditions.
Mixed
>65
years
impairment;
however,
they
younger
(<65
years).
thought
lower
threshold
for
developing
impairment
dementia.
Hereditary
also
range
beyond
proteinopathy
primarily
linked
abnormality.
Cases
might
different
course,
has
prognostic
relevance
obvious
implications
biomarker
therapy
development,
stratifying
patients
trials.
Abundant
filamentous
inclusions
of
tau
are
characteristic
more
than
20
neurodegenerative
diseases
that
collectively
termed
tauopathies.
Electron
cryo-microscopy
(cryo-EM)
structures
amyloid
filaments
from
human
brain
revealed
distinct
folds
characterise
many
different
diseases.
A
lack
laboratory-based
model
systems
to
generate
these
has
hampered
efforts
uncover
the
molecular
mechanisms
underlie
Here,
we
report
in
vitro
assembly
conditions
with
recombinant
replicate
both
Alzheimer's
disease
(AD)
and
chronic
traumatic
encephalopathy
(CTE),
as
determined
by
cryo-EM.
Our
results
suggest
post-translational
modifications
modulate
filament
assembly,
previously
observed
additional
densities
AD
CTE
may
arise
presence
inorganic
salts,
like
phosphates
sodium
chloride.
In
into
disease-relevant
will
facilitate
studies
determine
their
roles
diseases,
well
development
compounds
specifically
bind
or
prevent
formation.
Nature,
Год журнала:
2022,
Номер
605(7909), С. 310 - 314
Опубликована: Март 28, 2022
Abstract
Many
age-dependent
neurodegenerative
diseases,
such
as
Alzheimer’s
and
Parkinson’s,
are
characterized
by
abundant
inclusions
of
amyloid
filaments.
Filamentous
the
proteins
tau,
amyloid-β,
α-synuclein
transactive
response
DNA-binding
protein
(TARDBP;
also
known
TDP-43)
most
common
1,2
.
Here
we
used
structure
determination
cryogenic
electron
microscopy
to
show
that
residues
120–254
lysosomal
type
II
transmembrane
106B
(TMEM106B)
form
filaments
in
human
brains.
We
determined
structures
TMEM106B
from
a
number
brain
regions
22
individuals
with
deposits,
including
those
resulting
sporadic
inherited
tauopathies,
amyloid-β
amyloidoses,
synucleinopathies
TDP-43
proteinopathies,
well
frontal
cortex
3
normal
neurology
no
or
only
few
deposits.
observed
three
folds,
clear
relationships
between
folds
diseases.
correlated
presence
29-kDa
sarkosyl-insoluble
fragment
globular
cytoplasmic
inclusions,
detected
an
antibody
specific
carboxy-terminal
region
TMEM106B.
The
identification
brains
older,
but
not
younger,
indicates
they
manner.
Nature Communications,
Год журнала:
2022,
Номер
13(1)
Опубликована: Июль 13, 2022
Mammalian
prions
propagate
as
distinct
strains
and
are
composed
of
multichain
assemblies
misfolded
host-encoded
prion
protein
(PrP).
Here,
we
present
a
near-atomic
resolution
cryo-EM
structure
PrP
fibrils
in
highly
infectious
rod
preparations
isolated
from
the
brains
RML
prion-infected
mice.
We
found
that
rods
comprise
single-protofilament
helical
amyloid
coexist
with
twisted
pairs
same
protofilaments.
Each
rung
protofilament
is
formed
by
single
monomer
ordered
core
comprising
residues
94-225,
which
folds
to
create
two
asymmetric
lobes
N-linked
glycans
glycosylphosphatidylinositol
anchor
projecting
C-terminal
lobe.
The
overall
architecture
comparable
recently
reported
brain
hamsters
infected
263K
strain.
However,
there
marked
conformational
variations
could
result
differences
sequence
and/or
represent
distinguishing
features
strains.
PLoS Biology,
Год журнала:
2022,
Номер
20(7), С. e3001694 - e3001694
Опубликована: Июль 21, 2022
Strong
genetic
evidence
supports
an
imbalance
between
production
and
clearance
of
amyloid
β-protein
(Aβ)
in
people
with
Alzheimer
disease
(AD).
Microglia
that
are
potentially
involved
alternative
mechanisms
actually
integral
to
the
cascade.
Fluid
biomarkers
brain
imaging
place
accumulation
Aβ
at
beginning
molecular
clinical
changes
disease.
So
why
have
trials
anti-amyloid
therapies
not
provided
clear-cut
benefits
patients
AD?
Can
robustly
decrease
human
brain,
if
so,
could
this
lowering
be
too
little,
late?
These
central
questions
research
on
AD
being
urgently
addressed.
Nature,
Год журнала:
2023,
Номер
625(7993), С. 119 - 125
Опубликована: Ноя. 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.
