Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model.
R. Mendel,
Seiki Matsuno,
Alex Lu
и другие.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 27, 2024
ABSTRACT
S
ingle
large
s
cale
m
itochondrial
DNA
(mtDNA)
d
eletions
(SLSMD)
underlie
a
range
of
sporadic
or
maternally
inherited
primary
mitochondrial
diseases
having
significant
morbidity
and
mortality,
including
Pearson
syndrome,
Kearns-Sayre
Syndrome,
Chronic
Progressive
External
Ophthalmoplegia.
Therapeutic
development
has
been
hindered
by
limited
existing
knowledge
on
mtDNA
quality
control
lack
SLSMD
animal
models.
To
address
this
challenge,
we
utilized
the
C.
elegans
heteroplasmic
strain,
uaDf5,
to
objectively
screen
for
potential
therapies.
As
mitophagy
modulation
implicated
in
homeostasis,
screened
library
modulating
compounds
determine
their
comparative
effects
rescue
unfolded
protein
(UPR
mt
)
stress
induction
uaDf5
worms.
Interestingly,
Thiamine
was
discovered
be
an
effective
positive
control,
significantly
reducing
model.
Two
lead
therapeutic
candidates
from
were
Hemin
Celastrol
(Tripterin).
is
activating
anti-inflammatory
metabolic
modifying
natural
product
derived
compound,
that
rescued
multiple
fitness
outcomes
(thrashing,
development,
survival)
reduced
animals
mitophagy-dependent
fashion.
This
study
highlights
utility
worm
model
enable
preclinical
identification
candidate
leads
SLSMD-based
identifies
possible
serve
as
modulators
improve
health
specifically
reduce
heteroplasmy
levels
diseases.
Язык: Английский
Defective Neurogenesis in Lowe Syndrome is Caused by Mitochondria Loss and Cilia-related Sonic Hedgehog Defects
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 2, 2024
Abstract
Human
brain
development
is
a
complex
process
that
requires
intricate
coordination
of
multiple
cellular
and
developmental
events.
Dysfunction
lipid
metabolism
can
lead
to
neurodevelopmental
disorders.
Lowe
syndrome
(LS)
recessive
X-linked
disorder
associated
with
proximal
tubular
renal
disease,
congenital
cataracts
glaucoma,
central
nervous
system
delays.
Mutations
in
OCRL,
which
encodes
an
inositol
polyphosphate
5-phosphatase,
the
LS.
The
mechanism
responsible
for
neuronal
dysfunction
LS
unknown.
Here
we
show
depletion
mitochondrial
DNA
decrease
activities
result
differentiation
defects.
Increased
astrocytes,
are
secondary
responders
neurodegeneration,
observed
(iN)
cells
differentiated
from
patient-derived
iPSCs
mouse
model.
Inactivation
cilia-related
sonic
hedgehog
signaling,
organizes
pattern
differentiation,
OCRL
knockout,
iN
iPSCs,
Taken
together,
our
findings
indicate
impairment
ciliary
signaling
pathway
represent
novel
pathogenic
underlying
disrupted
Язык: Английский
Defective Neurogenesis in Lowe Syndrome is Caused by Mitochondria Loss and Cilia-related Sonic Hedgehog Defects
Опубликована: Дек. 19, 2024
Human
brain
development
is
a
complex
process
that
requires
intricate
coordination
of
multiple
cellular
and
developmental
events.
Dysfunction
lipid
metabolism
can
lead
to
neurodevelopmental
disorders.
Lowe
syndrome
(LS)
recessive
X-linked
disorder
associated
with
proximal
tubular
renal
disease,
congenital
cataracts
glaucoma,
central
nervous
system
delays.
Mutations
in
OCRL,
which
encodes
an
inositol
polyphosphate
5-phosphatase,
the
LS.
The
mechanism
responsible
for
neuronal
dysfunction
LS
unknown.
Here
we
show
depletion
mitochondrial
DNA
decrease
activities
result
differentiation
defects.
Increased
astrocytes,
are
secondary
responders
neurodegeneration,
observed
(iN)
cells
differentiated
from
patient-derived
iPSCs
mouse
model.
Inactivation
cilia-related
sonic
hedgehog
signaling,
organizes
pattern
differentiation,
OCRL
knockout,
iN
iPSCs,
Taken
together,
our
findings
indicate
impairment
ciliary
signaling
pathway
represent
novel
pathogenic
underlying
disrupted
Язык: Английский
Defective Neurogenesis in Lowe Syndrome is Caused by Mitochondria Loss and Cilia-related Sonic Hedgehog Defects
Опубликована: Дек. 19, 2024
Human
brain
development
is
a
complex
process
that
requires
intricate
coordination
of
multiple
cellular
and
developmental
events.
Dysfunction
lipid
metabolism
can
lead
to
neurodevelopmental
disorders.
Lowe
syndrome
(LS)
recessive
X-linked
disorder
associated
with
proximal
tubular
renal
disease,
congenital
cataracts
glaucoma,
central
nervous
system
delays.
Mutations
in
OCRL,
which
encodes
an
inositol
polyphosphate
5-phosphatase,
the
LS.
The
mechanism
responsible
for
neuronal
dysfunction
LS
unknown.
Here
we
show
depletion
mitochondrial
DNA
decrease
activities
result
differentiation
defects.
Increased
astrocytes,
are
secondary
responders
neurodegeneration,
observed
(iN)
cells
differentiated
from
patient-derived
iPSCs
mouse
model.
Inactivation
cilia-related
sonic
hedgehog
signaling,
organizes
pattern
differentiation,
OCRL
knockout,
iN
iPSCs,
Taken
together,
our
findings
indicate
impairment
ciliary
signaling
pathway
represent
novel
pathogenic
underlying
disrupted
Язык: Английский