bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Авг. 29, 2023
Abstract
The
loss
of
upper
and
lower
motor
neurons,
their
axons
is
central
to
the
function
death
in
amyotrophic
lateral
sclerosis
(ALS).
Due
diverse
range
genetic
environmental
factors
that
contribute
pathogenesis
ALS,
there
have
been
difficulties
developing
effective
therapies
for
ALS.
One
dichotomy
emerging
field
protection
neuronal
cell
soma
itself
does
not
prevent
axonal
vulnerability
degeneration,
suggesting
need
targeted
therapeutics
axon
degeneration.
Post-translational
modifications
protein
acetylation
can
alter
function,
stability
half-life
individual
proteins,
be
enzymatically
modified
by
histone
acetyltransferases
(HATs)
deacetyltransferases
(HDACs),
which
add,
or
remove
acetyl
groups,
respectively.
Maintenance
post-translational
microtubule
has
suggested
as
a
potential
mechanism
stabilise
neurodegeneration
This
study
utilized
an
orally
dosed
HDAC6
specific
inhibitor,
ACY-738,
deacetylation
stabilize
microtubules
mSOD1
G93A
mouse
model
Furthermore,
co-treatment
with
riluzole
was
performed
determine
any
effects
drug
interactions
potentially
enhance
preclinical
research
translation.
shows
ACY-738
treatment
increased
spinal
cord
mice,
reduced
neuron
degeneration
lumbar
female
ameliorated
reduction
peripheral
nerve
puncta
size,
but
did
overt
decline.
current
also
size
partially
restored
after
highlights
importance
measure
Highlights
inhibits
leads
mice.
reduces
restores
decline
Riluzole
Journal of Neurochemistry,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 18, 2024
Abstract
From
the
day
we
are
born,
nervous
system
is
subject
to
insult,
disease
and
degeneration.
Aberrant
phosphorylation
states
in
neurofilaments,
major
intermediate
filaments
of
neuronal
cytoskeleton,
accompany
mediate
many
pathological
processes
degenerative
disease.
Neuronal
damage,
degeneration
death
can
release
these
internal
components
extracellular
space
eventually
cerebrospinal
fluid
blood.
Sophisticated
assay
techniques
increasingly
able
detect
their
presence
at
very
low
levels,
increasing
utility
as
biomarkers
providing
insights
differential
diagnosis
for
earliest
stages
Although
a
variety
studies
focus
on
single
or
small
clusters
neurofilament
phosphorylated
epitopes,
this
review
offers
wider
perspective
landscape
heavy
subunit,
filament
component
both
ageing
image
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Дек. 30, 2024
Currently
there
are
no
effective
treatments
for
an
array
of
neurodegenerative
disorders
to
a
large
part
because
cell-based
models
fail
recapitulate
disease.
Here
we
develop
reproducible
human
iPSC-based
model
where
laser
axotomy
causes
retrograde
axon
degeneration
leading
neuronal
cell
death.
Time-lapse
confocal
imaging
revealed
that
damage
triggers
apoptotic
wave
mitochondrial
fission
proceeding
from
the
site
injury
soma.
We
demonstrate
this
is
locally
initiated
in
by
dual
leucine
zipper
kinase
(DLK).
find
and
resultant
death
entirely
dependent
on
phosphorylation
dynamin
related
protein
1
(DRP1)
downstream
DLK,
revealing
mechanism
which
DLK
can
drive
apoptosis.
Importantly,
show
CRISPR
mediated
Drp1
depletion
protects
mouse
retinal
ganglion
neurons
after
optic
nerve
crush.
Our
results
provide
platform
studying
neurons,
pinpoint
key
early
events
neural
potential
focus
therapeutic
intervention.
Heliyon,
Год журнала:
2024,
Номер
10(14), С. e34587 - e34587
Опубликована: Июль 1, 2024
The
loss
of
upper
and
lower
motor
neurons,
their
axons
is
central
to
the
function
death
in
amyotrophic
lateral
sclerosis
(ALS).
Due
diverse
range
genetic
environmental
factors
that
contribute
pathogenesis
ALS,
there
have
been
difficulties
developing
effective
therapies
for
ALS.
One
emerging
dichotomy
protection
neuronal
cell
soma
does
not
prevent
axonal
vulnerability
degeneration,
suggesting
need
targeted
therapeutics
axon
degeneration.
Post-translational
modifications
protein
acetylation
can
alter
function,
stability
half-life
individual
proteins,
be
enzymatically
modified
by
histone
acetyltransferases
(HATs)
deacetyltransferases
(HDACs),
which
add,
or
remove
acetyl
groups,
respectively.
Maintenance
post-translational
microtubule
has
suggested
as
a
mechanism
stabilize
axons,
neurodegeneration
This
study
used
an
orally
dosed
potent
HDAC6
inhibitor,
ACY-738,
deacetylation
microtubules
mSOD1G93A
mouse
model
Co-treatment
with
riluzole
was
performed
determine
any
effects
drug
interactions
potentially
enhance
preclinical
research
translation.
shows
ACY-738
treatment
increased
spinal
cord
mice,
reduced
neuron
degeneration
female
ameliorated
reduction
peripheral
nerve
puncta
size,
but
did
overt
decline.
current
also
size
partially
restored
after
highlights
importance
co-treatment
measure
potential
Cells,
Год журнала:
2024,
Номер
13(24), С. 2076 - 2076
Опубликована: Дек. 17, 2024
Amyotrophic
lateral
sclerosis
(ALS),
commonly
known
as
motor
neuron
disease,
is
a
neurodegenerative
disorder
characterized
by
the
progressive
degeneration
of
both
upper
and
lower
neurons.
This
pathological
process
results
in
muscle
weakness
can
culminate
paralysis.
To
date,
precise
etiology
ALS
remains
unclear.
However,
burgeoning
body
research
indicates
that
axonal
dysfunction
pivotal
element
pathogenesis
significantly
influences
progression
disease.
Dysfunction
axons
result
impediments
to
nerve
impulse
transmission,
leading
impairment,
atrophy,
other
associated
complications
severely
compromise
patients’
quality
life
survival
prognosis.
In
this
review,
we
concentrate
on
several
key
areas:
ultrastructure
axons,
mechanisms
ALS,
impact
impaired
transport
disease
potential
for
regeneration
within
central
nervous
system
(CNS).
Our
objective
achieve
more
holistic
profound
understanding
multifaceted
role
play
thereby
offering
intricate
refined
perspective
targeted
therapeutic
interventions.
