Neurobiology of Disease,
Год журнала:
2025,
Номер
unknown, С. 106804 - 106804
Опубликована: Янв. 1, 2025
Abnormal
tau
phosphorylation
is
a
key
mechanism
in
neurodegenerative
diseases.
Evidence
implicates
infectious
agents,
such
as
Herpes
Simplex
Virus
1
(HSV-1),
co-factors
the
onset
or
progression
of
diseases,
including
Alzheimer's
disease.
This
has
led
to
divergence
field
regarding
contribution
viruses
etiology
Research
indicates
that
may
function
risk
factors
driving
disease
rather
than
playing
causative
role.
Investigating
HSV-1
abnormal
important
for
understanding
role
agents
neurodegeneration.
We
generated
cellular
models
acute,
latent
infection,
and
viral
reactivation
from
latency
cortical
brain
organoids
investigated
interplay
between
infection
by
employing
human
induced
pluripotent
stem
cell
(iPSC)-derived
monolayer
neuronal
cultures
organoids.
Acute
with
strains
17syn+
KOS
caused
nuclear
accumulation
phosphorylated
(p-tau)
neurons
neural
precursor
cells.
Antivirals
prevented
p-tau.
Viral
was
accompanied
translocation
Chromatin
immunoprecipitation
analysis
indicated
an
interaction
p-tau
chromatin.
A
reduction
abundance
component
speckles
their
loss
organized
morphology
low
host
chromatin
density
regions
observed,
strain-specific
differences.
followed
increase
BRSKs
TAOKs,
kinases
known
phosphorylate
tau.
These
findings
show
demonstrate
ability
activate
mechanisms
are
observed
Signal Transduction and Targeted Therapy,
Год журнала:
2023,
Номер
8(1)
Опубликована: Ноя. 10, 2023
Abstract
Proper
subcellular
localization
is
crucial
for
the
functioning
of
biomacromolecules,
including
proteins
and
RNAs.
Nuclear
transport
a
fundamental
cellular
process
that
regulates
many
macromolecules
within
nuclear
or
cytoplasmic
compartments.
In
humans,
approximately
60
are
involved
in
transport,
nucleoporins
form
membrane-embedded
pore
complexes,
karyopherins
cargoes
through
these
Ran
system
ensure
directed
rapid
transport.
Many
play
additional
essential
roles
mitosis,
biomolecular
condensation,
gene
transcription.
Dysregulation
linked
to
major
human
diseases
such
as
cancer,
neurodegenerative
diseases,
viral
infections.
Selinexor
(KPT-330),
an
inhibitor
targeting
export
factor
XPO1
(also
known
CRM1),
was
approved
2019
treat
two
types
blood
cancers,
dozens
clinical
trials
ongoing.
This
review
summarizes
three
decades
research
data
this
field
but
focuses
on
structure
function
individual
from
recent
studies,
providing
cutting-edge
holistic
view
role
health
disease.
In-depth
knowledge
rapidly
evolving
has
potential
bring
new
insights
into
biology,
pathogenic
mechanisms,
therapeutic
approaches.
The EMBO Journal,
Год журнала:
2025,
Номер
44(3), С. 613 - 638
Опубликована: Янв. 9, 2025
Dysregulation
of
RNA
processing
has
in
recent
years
emerged
as
a
significant
contributor
to
neurodegeneration.
The
diverse
mechanisms
and
molecular
functions
underlying
underscore
the
essential
role
regulation
maintaining
neuronal
health
function.
molecules
are
bound
by
RNA-binding
proteins
(RBPs),
interactions
between
RNAs
RBPs
commonly
affected
In
this
review,
we
highlight
progress
understanding
dysregulated
RNA-processing
pathways
causes
RBP
dysfunction
across
various
neurodegenerative
diseases.
We
discuss
both
established
emerging
RNA-mediated
neuropathogenesis
rapidly
evolving
field.
Furthermore,
explore
development
potential
RNA-targeting
therapeutic
approaches
for
treatment
FEBS Journal,
Год журнала:
2021,
Номер
289(22), С. 7234 - 7245
Опубликована: Июль 10, 2021
Complex,
multistep
biochemical
reactions
that
routinely
take
place
in
our
cells
require
high
concentrations
of
enzymes,
substrates,
and
other
structural
components
to
proceed
efficiently
typically
chemical
environments
can
inhibit
their
immediate
vicinity.
Eukaryotic
solve
these
problems
by
restricting
such
into
diffusion‐restricted
compartments
within
the
cell
called
organelles
be
separated
from
environment
a
lipid
membrane,
or
membrane‐less
form
through
liquid–liquid
phase
separation
(LLPS).
One
most
easily
noticeable
earliest
discovered
organelle
is
nucleus,
which
harbors
genetic
material
where
transcription
RNA
polymerases
produces
messenger
RNAs
plethora
noncoding
RNAs,
turn
are
required
for
translation
mRNAs
cytoplasm.
The
interior
nucleus
not
uniform
soup
biomolecules
rather
consists
variety
bodies,
as
nucleolus,
nuclear
speckles
(NS),
paraspeckles,
Cajal
histone
locus
more.
In
this
review,
we
will
focus
on
NS
with
an
emphasis
recent
developments
including
own
findings
about
formation
two
large
IDR‐rich
proteins
SON
SRRM2.
Nucleic Acids Research,
Год журнала:
2022,
Номер
50(15), С. 8599 - 8614
Опубликована: Авг. 5, 2022
Abstract
SRRM2
is
a
nuclear-speckle
marker
containing
multiple
disordered
domains,
whose
dysfunction
associated
with
several
human
diseases.
Using
mainly
EGFP-SRRM2
knock-in
HEK293T
cells,
we
show
that
forms
biomolecular
condensates
satisfying
most
hallmarks
of
liquid-liquid
phase
separation,
including
spherical
shape,
dynamic
rearrangement,
coalescence
and
concentration
dependence
supported
by
in
vitro
experiments.
Live-cell
imaging
shows
organizes
nuclear
speckles
along
the
cell
cycle.
As
bona-fide
splicing
factor
present
spliceosome
structures,
deficiency
induces
skipping
cassette
exons
short
introns
weak
splice
sites,
tending
to
change
large
protein
domains.
In
THP-1
myeloid-like
depletion
compromises
viability,
upregulates
differentiation
markers,
sensitizes
cells
anti-leukemia
drugs.
FES
isoform
attenuates
innate
inflammatory
responses,
MUC1
isoforms
undergo
shedding
oncogenic
properties.
We
conclude
acts
as
scaffold
organize
speckles,
regulating
alternative
immunity
homeostasis.
Journal of Cell Science,
Год журнала:
2022,
Номер
135(13)
Опубликована: Июль 1, 2022
Nuclear
speckles
are
dynamic
membraneless
bodies
located
in
the
cell
nucleus.
They
harbor
RNAs
and
proteins,
many
of
which
splicing
factors,
that
together
display
complex
biophysical
properties
dictating
nuclear
speckle
formation
maintenance.
Although
these
were
discovered
decades
ago,
only
recently
has
in-depth
genomic
analysis
begun
to
unravel
their
essential
functions
modulation
gene
activity.
Major
advancements
mapping
techniques
combined
with
microscopy
approaches
have
enabled
insights
into
roles
may
play
enhancing
expression,
how
positioning
specific
landmarks
can
regulate
expression
RNA
processing.
Some
studies
drawn
a
link
between
disease.
Certain
maladies
either
involve
directly
or
dictate
localization
reorganization
factors.
This
is
most
striking
during
viral
infection,
as
viruses
alter
entire
architecture
highjack
host
machinery.
As
discussed
this
Review,
represent
fascinating
target
study
not
reveal
links
positioning,
genome
subcompartments
activity,
but
also
potential
for
therapeutics.
Proceedings of the National Academy of Sciences,
Год журнала:
2022,
Номер
119(15)
Опубликована: Апрель 4, 2022
In
neurodegenerative
diseases
including
Alzheimer’s
and
amyotrophic
lateral
sclerosis,
proteins
that
bind
RNA
are
found
in
aggregated
forms
autopsied
brains.
Evidence
suggests
aids
nucleation
of
these
pathological
aggregates;
however,
the
mechanism
has
not
been
investigated
at
level
atomic
structure.
Here,
we
present
3.4-Å
resolution
structure
fibrils
full-length
recombinant
tau
protein
presence
RNA,
determined
by
electron
cryomicroscopy
(cryo-EM).
The
reveals
familiar
in-register
cross-β
amyloid
scaffold
but
with
a
small
fibril
core
spanning
residues
Glu391
to
Ala426,
region
disordered
fuzzy
coat
all
previously
studied
polymorphs.
is
bound
on
surface
positively
charged
Arg406
His407
runs
parallel
axis.
dissolve
when
RNase
added,
showing
necessary
for
integrity.
While
this
cannot
exist
simultaneously
structures
extracted
from
patients’
brains,
it
could
conceivably
account
nucleating
effects
cofactors
followed
remodeling
as
mature.
Molecular Neurodegeneration,
Год журнала:
2022,
Номер
17(1)
Опубликована: Окт. 17, 2022
Pathological
tau
aggregation
is
a
primary
neuropathological
feature
of
many
neurodegenerative
diseases.
Intriguingly,
despite
the
common
presence
aggregates
in
these
diseases
affected
brain
regions,
clinical
symptoms,
and
morphology,
conformation,
isoform
ratio
present
varies
widely.
The
tau-mediated
disease
mechanisms
that
drive
are
still
unknown.
Tau
interactome
studies
critically
important
for
understanding
tauopathy.
They
reveal
interacting
partners
define
pathways,
interactions
provide
potential
insight
into
cellular
environment
protein
during
pathological
aggregation.
Here
we
combined
analysis
12
human
tissue,
cell
culture
models
rodent
disease.
Together,
identified
2084
proteins
interact
with
tissue
1152
Our
revealed
consistent
enrichment
between
involved
RNA
binding,
ribosome,
proteasome
function.
Comparison
substantial
differences
two
species.
We
also
performed
second
to
identify
enriched
neurons
containing
granulovacuolar
degeneration
or
neurofibrillary
tangle
pathology.
These
results
timed
dysregulation
as
pathology
develops.
binding
proteins,
particularly
HNRNPs,
emerged
early
disease-associated
interactors
therefore
may
have
an
role
driving