Cell Reports,
Год журнала:
2021,
Номер
34(1), С. 108588 - 108588
Опубликована: Янв. 1, 2021
Axonal
degeneration
is
responsible
for
disease
progression
and
accumulation
of
disability
in
many
neurodegenerative
conditions.
The
axonal
degenerative
process
can
generate
a
metastable
pool
damaged
axons
that
remain
structurally
functionally
viable
but
fated
to
degenerate
the
absence
external
intervention.
SARM1,
an
NADase
depletes
energy
stores
upon
activation,
central
driver
evolutionarily
conserved
program
degeneration.
We
identify
potent
selective
small
molecule
isoquinoline
inhibitor
SARM1
recapitulates
SARM1-/-
phenotype
protects
from
induced
by
axotomy
or
mitochondrial
dysfunction.
inhibition
post-mitochondrial
injury
with
rotenone
allows
recovery
rescues
already
entered
state.
conclude
molecules
has
potential
treat
axonopathies
peripheral
nervous
systems
preventing
allowing
functional
damaged,
viable,
axons.
Frontiers in Pharmacology,
Год журнала:
2022,
Номер
13
Опубликована: Март 28, 2022
Since
the
first
clinical
trials
conducted
after
World
War
II,
chemotherapeutic
drugs
have
been
extensively
used
in
clinic
as
main
cancer
treatment
either
alone
or
an
adjuvant
therapy
before
and
surgery.
Although
use
of
improved
survival
patients,
these
are
notorious
for
causing
many
severe
side
effects
that
significantly
reduce
efficacy
anti-cancer
patients'
quality
life.
Many
widely
chemotherapy
including
platinum-based
agents,
taxanes,
vinca
alkaloids,
proteasome
inhibitors,
thalidomide
analogs
may
cause
direct
indirect
neurotoxicity.
In
this
review
we
discuss
on
peripheral
central
nervous
systems,
neuropathic
pain,
chemobrain,
enteric
neuropathy,
well
nausea
emesis.
Understanding
mechanisms
involved
chemotherapy-induced
neurotoxicity
is
crucial
development
can
protect
system,
symptoms
experienced
by
millions
improve
outcome
Brain,
Год журнала:
2021,
Номер
144(10), С. 3226 - 3238
Опубликована: Май 6, 2021
Abstract
Axonal
degeneration
is
an
early
and
ongoing
event
that
causes
disability
disease
progression
in
many
neurodegenerative
disorders
of
the
peripheral
central
nervous
systems.
Chemotherapy-induced
neuropathy
(CIPN)
a
major
cause
morbidity
main
dose
reductions
discontinuations
cancer
treatment.
Preclinical
evidence
indicates
activation
Wallerian-like
pathway
driven
by
sterile
alpha
TIR
motif
containing
1
(SARM1)
responsible
for
axonopathy
CIPN.
SARM1
driver
evolutionarily
conserved
programme
axonal
downstream
chemical,
inflammatory,
mechanical
or
metabolic
insults
to
axon.
contains
intrinsic
NADase
enzymatic
activity
essential
its
pro-degenerative
functions,
making
it
compelling
therapeutic
target
treat
neurodegeneration
characterized
axonopathies
Small
molecule
inhibitors
have
potential
prevent
provide
transformational
disease-modifying
treatment
these
disorders.
Using
biochemical
assay
we
identified
novel
series
potent
selective
irreversible
isothiazole
protected
rodent
human
axons
vitro.
In
sciatic
nerve
axotomy,
observed
decreased
rise
cADPR
plasma
neurofilament
light
chain
released
from
injured
nerves
vivo.
mouse
paclitaxel
model
CIPN
determined
Sarm1
knockout
mice
prevented
loss
function,
assessed
sensory
action
amplitudes
tail
nerve,
gene-dosage-dependent
manner.
model,
intraepidermal
fibres
induced
provided
partial
protection
function
amplitude
allodynia.
Molecular Neurodegeneration,
Год журнала:
2022,
Номер
17(1)
Опубликована: Янв. 6, 2022
Abstract
Background
In
response
to
injury,
neurons
activate
a
program
of
organized
axon
self-destruction
initiated
by
the
NAD
+
hydrolase,
SARM1.
healthy
SARM1
is
autoinhibited,
but
single
amino
acid
changes
can
abolish
autoinhibition
leading
constitutively
active
enzymes
that
promote
degeneration
when
expressed
in
cultured
neurons.
Methods
To
investigate
whether
naturally
occurring
human
variants
might
disrupt
and
potentially
contribute
risk
for
neurodegenerative
disease,
we
assayed
enzymatic
activity
all
42
rare
alleles
identified
among
8507
amyotrophic
lateral
sclerosis
(ALS)
patients
9671
controls.
We
then
intrathecally
injected
mice
with
virus
expressing
constructs
test
capacity
an
ALS-associated
variant
neurodegeneration
vivo.
Results
Twelve
out
missense
or
small
in-frame
deletions
exhibit
constitutive
NADase
activity,
including
more
than
half
those
are
unique
ALS
occur
multiple
patients.
There
>
5-fold
enrichment
compared
Expression
dorsal
root
ganglion
(DRG)
pro-degenerative
cytotoxic.
Intrathecal
injection
AAV
common
reference
allele
innocuous
mice,
construct
harboring
V184G
,
found
most
frequently
patients,
causes
loss,
motor
dysfunction,
sustained
neuroinflammation.
Conclusions
These
results
implicate
hypermorphic
as
candidate
genetic
factors
other
conditions.
The Journal of Cell Biology,
Год журнала:
2020,
Номер
219(8)
Опубликована: Июль 1, 2020
Neuroinflammation
and
necroptosis
are
major
contributors
to
neurodegenerative
disease,
axon
dysfunction
degeneration
is
often
an
initiating
event.
SARM1
the
central
executioner
of
pathological
degeneration.
Here,
we
demonstrate
functional
mechanistic
links
among
these
three
pro-degenerative
processes.
In
a
neuroinflammatory
model
glaucoma,
TNF-α
induces
SARM1-dependent
degeneration,
oligodendrocyte
loss,
subsequent
retinal
ganglion
cell
death.
also
triggers
in
sensory
neurons
via
noncanonical
necroptotic
signaling
mechanism.
MLKL
final
canonical
necroptosis;
however,
axonal
necroptosis,
does
not
directly
trigger
Instead,
loss
survival
factors
NMNAT2
STMN2
activate
NADase
activity,
which
leads
calcium
influx
Hence,
findings
define
specialized
form
necroptosis.
The
demonstration
that
signals
can
act
locally
stimulate
identifies
therapeutically
targetable
mechanism
by
neuroinflammation
disease.
Trends in Pharmacological Sciences,
Год журнала:
2020,
Номер
41(4), С. 281 - 293
Опубликована: Фев. 24, 2020
Attempts
to
develop
neuroprotective
treatments
for
neurodegenerative
disorders
have
not
yet
been
clinically
successful.
Axonal
degeneration
has
recognized
as
a
predominant
driver
of
disability
and
disease
progression
in
central
nervous
system
(CNS)
diseases
such
amyotrophic
lateral
sclerosis
(ALS),
multiple
sclerosis,
Parkinson's
disease,
peripheral
(PNS)
chemotherapy-induced,
diabetic,
inherited
neuropathies,
ocular
disorders,
glaucoma.
In
recent
years,
sterile
alpha
TIR
motif
containing
1
(SARM1)
emerged
the
first
compelling
axonal-specific
target
therapeutic
intervention.
this
review,
we
discuss
role
axonal
with
focus
on
SARM1
discovery
its
intrinsic
enzymatic
function.
Establishment
neurofilament
light
chain
(NfL)
reliable
biomarker
damage,
availability
an
ultrasensitive
method
measuring
NfL
plasma
or
serum,
provide
translational
tools
make
development
protective,
inhibitors
viable
approach
treat
disorders.
