Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence
Acta Neuropathologica Communications,
Journal Year:
2025,
Volume and Issue:
13(1)
Published: March 8, 2025
Abstract
TDP-43
mislocalization
and
aggregation
are
key
pathological
features
of
amyotrophic
lateral
sclerosis
(ALS)-
frontotemporal
dementia
(FTD).
However,
existing
transgenic
hTDP-43
WT
or
∆NLS-overexpression
animal
models
primarily
focus
on
late-stage
proteinopathy.
To
complement
these
to
study
the
early-stage
motor
neuron-specific
pathology
during
pre-symptomatic
phases
disease
progression,
we
generated
a
new
endogenous
knock-in
(KI)
mouse
model
using
combination
CRISPR/Cas9
FLEX
Cre-switch
strategy
for
conditional
expression
mislocalized
Tdp-43∆NLS
variant
Tdp-43.
This
is
expressed
either
in
whole
body
(WB)
specifically
neurons
(MNs)
two
distinct
models.
These
mice
exhibit
loss
nuclear
Tdp-43,
with
concomitant
cytosolic
accumulation
targeted
cells,
leading
increased
DNA
double-strand
breaks
(DSBs),
signs
inflammation,
associated
cellular
senescence.
Notably,
unlike
which
functionally
interacts
Xrcc4
Ligase
4,
DSB
repair
proteins
non-homologous
end-joining
(NHEJ)
pathway,
mutant
sequesters
them
into
aggregates,
exacerbating
neuronal
damage
brain.
The
also
myogenic
degeneration
hindlimb
soleus
muscles
deficits,
consistent
characteristics
neuron
(MND).
Our
findings
reveal
progressive
degenerative
mechanisms
expressing
mutant,
independent
Tdp-43
overexpression
other
confounding
factors.
Thus,
this
unique
KI
model,
displays
molecular
phenotypic
proteinopathy,
offers
significant
opportunity
characterize
progression
MND
further
opens
avenues
developing
repair-targeted
approaches
treating
pathology-linked
neurodegenerative
diseases.
Language: Английский
Technical Assessment of Motor and Behavioral Tests in Rodent Models of Multiple Sclerosis
Journal of Integrative Neuroscience,
Journal Year:
2025,
Volume and Issue:
24(2)
Published: Feb. 21, 2025
Background:
Multiple
sclerosis
(MS)
is
a
neurodegenerative
disorder
characterized
by
progressive
motor
and
cognitive
impairments,
affecting
millions
worldwide.
It
significantly
reduces
patients’
quality
of
life
imposes
burden
on
health
systems.
Despite
advances
in
understanding
MS,
there
no
cure,
highlighting
the
need
for
effective
therapeutic
strategies.
Preclinical
animal
models
are
critical
gaining
insights
into
MS
pathophysiology
treatments.
However,
these
fail
to
fully
replicate
complexity
human
making
it
essential
choose
appropriate
behavioral
tests
evaluate
their
efficacy.
Purpose:
This
review
examines
various
used
preclinical
models,
discussing
strengths
limitations.
The
goal
guide
researchers
selecting
most
while
providing
how
performed
analyzed.
Methods:
We
reviewed
detailing
test
procedures
evaluating
advantages
disadvantages.
Results:
offers
comprehensive
overview
that
aids
choosing
suitable
studies,
improving
accuracy
reliability
research.
Conclusions:
Understanding
limitations
crucial
informed
decisions,
leading
better
experimental
designs
and,
ultimately,
more
interventions
MS.
Language: Английский
TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects
Research Square (Research Square),
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 1, 2025
Abstract
TDP-43
is
a
nuclear
protein
encoded
by
the
TARDBP
gene,
which
forms
pathological
aggregates
in
various
neurodegenerative
diseases,
collectively
known
as
proteinopathies,
including
amyotrophic
lateral
sclerosis
(ALS)
and
frontotemporal
dementia
(FTD).
These
diseases
are
characterized
multiple
mechanisms,
with
disruptions
lipid
regulatory
pathways
emerging
critical
factor.
However,
role
of
regulation
brain
homeostasis
potential
connection
dysfunction
to
myelin
alterations
proteionopathies
remain
poorly
understood,
despite
fact
that
lipids,
particularly
cholesterol,
comprise
nearly
70%
myelin.
To
investigate
causal
relationship
between
cholesterol
homeostasis,
we
conducted
multi-omics
analyses
(lipidomics,
transcriptomics,
functional
splicing)
on
frontal
cortex
from
TardbpM323K/M323K
knock-in
mouse
model.
Lipidomic
analysis
revealed
related
membrane
composition
droplet
accumulation,
affecting
cholesterol-related
species.
We
found
higher
droplets
accumulation
primary
fibroblast
derived
these
mice,
well
mutant
mice.
Similarly,
immunohistochemical
detection
marker
was
post-mortem
cortex,
gray
white
matter,
FTLD-TDP
patients
compared
non-neurological
controls.
Transcriptomic
showed
pathology
led
transcriptional
dysregulation
genes
essential
for
production
maintenance.
identified
impaired
metabolism,
mainly
through
downregulation
endogenous
synthesis,
alongside
upregulated
transport
pathways,
further
replicated
transcriptomic
datasets.
Collectively,
our
findings
suggest
disrupts
potentially
compromising
integrity.
Language: Английский
Challenges of modelling TDP-43 pathology in mice
Mammalian Genome,
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 29, 2025
Language: Английский
Progress in the role and mechanism of TDP-43
New discovery.,
Journal Year:
2024,
Volume and Issue:
unknown, P. 1 - 8
Published: Sept. 20, 2024
Background:
TAR
DNA-binding
protein
43
kDa
(TDP-43)
has
been
shown
to
play
an
important
role
in
the
development
of
neurodegenerative
diseases,
but
mechanism
is
still
under
study.
Methods:
By
utilizing
“TDP43”,
“disease”,
and
“mechanism”
as
keywords,
200
related
studies
were
retrieved
downloaded
from
Pubmed
database,
including
60
articles.
We
summarized
progress
understanding
TDP-43
over
past
two
years,
focusing
on
disease
systems
classification
upstream
downstream,
connection,
improvement,
formation.
Results:
TDP-43,
when
abnormally
aggregated,
phosphorylated,
or
mislocalized,
plays
a
key
pathological
diseases.
Additionally,
its
impact
normal
reproductive
cell
formation,
development,
quantity,
activity,
well
insulin
secretion
activation
intestinal
epithelial
necrosis,
should
not
be
overlooked.
Mechanistically,
we
identified
relationship
between
expression
factors,
Enterovirus
D68
(EV-D68),
Heterogeneous
Nuclear
Ribonucleoprotein
D
(HNRNPD
AUF1),
Endoplasmic
Reticulum
Protein
57
(ERp57),
Progranulin
(PGRN),
downstream
factors
such
Meiotic
Recombination
Spo11
(Spo11),
AMP-Activated
Kinase
(AMPK),
Double-Strand-Break
Repair
Rad21
Homolog
(Rad21L),
IκB
(IKK),
TDP-43.
Conclusion:
neurodegeneration,
which,
phosphorylation,
EV-d68,
HNRNPD.
Language: Английский