International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(9), С. 4969 - 4969
Опубликована: Май 2, 2024
Tau
protein
misfolding
and
aggregation
are
pathological
hallmarks
of
Alzheimer's
disease
over
twenty
neurodegenerative
disorders.
However,
the
molecular
mechanisms
tau
in
vivo
remain
incompletely
understood.
There
two
types
aggregates
brain:
soluble
(oligomers
protofibrils)
insoluble
filaments
(fibrils).
Compared
to
filamentous
aggregates,
more
toxic
exhibit
prion-like
transmission,
providing
seeds
for
templated
misfolding.
Curiously,
its
native
state,
is
a
highly
soluble,
heat-stable
that
does
not
form
fibrils
by
itself,
even
when
hyperphosphorylated.
In
vitro
studies
have
found
negatively
charged
molecules
such
as
heparin,
RNA,
or
arachidonic
acid
generally
required
induce
aggregation.
Two
recent
breakthroughs
provided
new
insights
into
mechanisms.
First,
an
intrinsically
disordered
protein,
undergo
liquid-liquid
phase
separation
(LLPS)
both
inside
cells.
Second,
cryo-electron
microscopy
has
revealed
diverse
fibrillar
conformations
associated
with
different
Nonetheless,
only
core
structurally
resolved,
remainder
appears
"fuzzy
coat".
From
this
review,
it
further
(1)
clarify
role
LLPS
aggregation;
(2)
unveil
structural
features
aggregates;
(3)
understand
involvement
fuzzy
coat
regions
oligomer
fibril
formation.
Proceedings of the National Academy of Sciences,
Год журнала:
2023,
Номер
120(51)
Опубликована: Дек. 15, 2023
The
amyotrophic
lateral
sclerosis/parkinsonism-dementia
complex
(ALS/PDC)
of
the
island
Guam
and
Kii
peninsula
Japan
is
a
fatal
neurodegenerative
disease
unknown
cause
that
characterized
by
presence
abundant
filamentous
tau
inclusions
in
brains
spinal
cords.
Here,
we
used
electron
cryo-microscopy
to
determine
structures
filaments
from
cerebral
cortex
three
cases
ALS/PDC
eight
Kii,
as
well
cord
two
cases.
Tau
had
chronic
traumatic
encephalopathy
(CTE)
fold,
with
variable
amounts
Type
I
II
filaments.
Paired
helical
were
also
found
corticobasal
degeneration
fold
one
case.
We
identified
new
III
CTE
filament,
where
protofilaments
pack
against
each
other
an
antiparallel
fashion.
third
known
tauopathy
CTE-type
cortical
layers
II/III,
others
being
subacute
sclerosing
panencephalitis.
Because
these
tauopathies
are
believed
have
environmental
causes,
our
findings
support
hypothesis
caused
exogenous
factors.
Chemical Reviews,
Год журнала:
2023,
Номер
123(21), С. 12254 - 12311
Опубликована: Окт. 24, 2023
Protein
misfolding
and
aggregation,
a
key
contributor
to
the
progression
of
numerous
neurodegenerative
diseases,
results
in
functional
deficiencies
creation
harmful
intermediates.
Detailed
visualization
this
process
is
paramount
importance
for
improving
our
understanding
disease
mechanisms
development
potential
therapeutic
strategies.
While
vitro
studies
using
purified
proteins
have
been
instrumental
delivering
significant
insights
into
protein
misfolding,
behavior
these
complex
milieu
living
cells
often
diverges
significantly
from
such
simplified
environments.
Biomedical
imaging
performed
cell
provides
cellular-level
information
with
high
physiological
pathological
relevance,
surpassing
depth
attainable
through
methods.
This
review
highlights
variety
methodologies
used
scrutinize
within
biological
systems.
includes
optical-based
methods,
strategies
leaning
on
mass
spectrometry,
in-cell
nuclear
magnetic
resonance,
cryo-electron
microscopy.
Recent
advancements
techniques
notably
deepened
processes
features
resulting
misfolded
species
cells.
The
fields
promises
catalyze
further
breakthroughs
comprehension
interventions.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Июнь 17, 2023
Aggregation
of
the
protein
tau
defines
tauopathies,
which
include
Alzheimer's
disease
and
frontotemporal
dementia.
Specific
neuronal
subtypes
are
selectively
vulnerable
to
aggregation
subsequent
dysfunction
death,
but
underlying
mechanisms
unknown.
To
systematically
uncover
cellular
factors
controlling
accumulation
aggregates
in
human
neurons,
we
conducted
a
genome-wide
CRISPRi-based
modifier
screen
iPSC-derived
neurons.
The
uncovered
expected
pathways,
including
autophagy,
also
unexpected
UFMylation
GPI
anchor
synthesis.
We
discover
that
E3
ubiquitin
ligase
CUL5
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(9), С. 4969 - 4969
Опубликована: Май 2, 2024
Tau
protein
misfolding
and
aggregation
are
pathological
hallmarks
of
Alzheimer's
disease
over
twenty
neurodegenerative
disorders.
However,
the
molecular
mechanisms
tau
in
vivo
remain
incompletely
understood.
There
two
types
aggregates
brain:
soluble
(oligomers
protofibrils)
insoluble
filaments
(fibrils).
Compared
to
filamentous
aggregates,
more
toxic
exhibit
prion-like
transmission,
providing
seeds
for
templated
misfolding.
Curiously,
its
native
state,
is
a
highly
soluble,
heat-stable
that
does
not
form
fibrils
by
itself,
even
when
hyperphosphorylated.
In
vitro
studies
have
found
negatively
charged
molecules
such
as
heparin,
RNA,
or
arachidonic
acid
generally
required
induce
aggregation.
Two
recent
breakthroughs
provided
new
insights
into
mechanisms.
First,
an
intrinsically
disordered
protein,
undergo
liquid-liquid
phase
separation
(LLPS)
both
inside
cells.
Second,
cryo-electron
microscopy
has
revealed
diverse
fibrillar
conformations
associated
with
different
Nonetheless,
only
core
structurally
resolved,
remainder
appears
"fuzzy
coat".
From
this
review,
it
further
(1)
clarify
role
LLPS
aggregation;
(2)
unveil
structural
features
aggregates;
(3)
understand
involvement
fuzzy
coat
regions
oligomer
fibril
formation.
