bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2023,
Volume and Issue:
unknown
Published: Nov. 17, 2023
Abstract
Dominant
variants
in
WFS1
,
a
gene
coding
for
the
mitochondria-associated
endoplasmic
reticulum
(ER)
membrane
(MAM)
resident
protein
Wolframin,
have
been
associated
with
Wolfram-like
syndrome
(WLS).
In
vitro
and
vivo
loss
results
reduced
ER
to
mitochondria
calcium
(Ca
2+
)
transfer,
mitochondrial
dysfunction,
enhanced
autophagy
mitophagy.
However,
WLS
pathological
context,
whether
mutant
triggers
same
cellular
processes
is
unknown.
Here,
we
show
that,
human
fibroblasts
murine
neuronal
cultures,
E864K
leads
decreases
bioenergetics
Ca
uptake,
deregulation
of
quality
system
mechanisms,
alteration
autophagic
flux.
Moreover,
Wfs1
mouse,
these
alterations
are
concomitant
decrease
MAM
number.
These
findings
reveal
pathophysiological
similarities
between
WS
WLS,
highlighting
importance
MAM’s
integrity
functionality.
It
may
open
new
treatment
perspectives,
until
now
non-existent,
patients
WLS.
International Journal of Molecular Sciences,
Journal Year:
2021,
Volume and Issue:
22(24), P. 13356 - 13356
Published: Dec. 12, 2021
Rare
genetic
diseases
are
a
group
of
pathologies
with
often
unmet
clinical
needs.
Even
if
rare
by
single
disease
(from
1/2000
to
1/more
than
1,000,000),
the
total
number
patients
concerned
account
for
approximatively
400
million
peoples
worldwide.
Finding
treatments
remains
challenging
due
complexity
these
diseases,
small
and
challenge
in
conducting
trials.
Therefore,
innovative
preclinical
research
strategies
required.
The
zebrafish
has
emerged
as
powerful
animal
model
investigating
diseases.
Zebrafish
combines
conserved
vertebrate
characteristics
high
rate
breeding,
limited
housing
requirements
low
costs.
More
84%
human
genes
responsible
present
an
orthologue,
suggesting
that
majority
could
be
modelized
zebrafish.
In
this
review,
we
emphasize
unique
advantages
models
over
other
vivo
models,
particularly
underlining
throughput
phenotypic
capacity
therapeutic
screening.
We
briefly
introduce
how
generation
transgenic
lines
gene-modulating
technologies
can
used
Then,
describe
phenotyped
using
state-of-the-art
technologies.
Two
prototypic
examples
illustrate
play
critical
role
deciphering
underlying
mechanisms
their
use
identify
solutions.
Cells,
Journal Year:
2022,
Volume and Issue:
11(12), P. 1963 - 1963
Published: June 18, 2022
Calcium
ions
(Ca2+)
operate
as
important
messengers
in
the
cell,
indispensable
for
signaling
underlying
numerous
cellular
processes
all
of
cell
types
human
body.
In
neurons,
Ca2+
is
crucial
regulating
synaptic
transmission
and
learning
memory
formation.
Hence,
dysregulation
intracellular
homeostasis
results
a
broad
range
disorders,
including
cancer
neurodegeneration.
A
major
source
endoplasmic
reticulum
(ER),
which
has
close
contacts
with
other
organelles,
mitochondria.
this
review,
we
focus
on
emerging
role
at
ER–mitochondrial
interface
two
different
neurodegenerative
diseases,
namely
Alzheimer’s
disease
Wolfram
syndrome.
Both
these
diseases
share
some
common
hallmarks
early
stages,
alterations
ER
mitochondrial
handling,
dysfunction
increased
Reactive
oxygen
species
(ROS)
production.
This
indicates
that
similar
mechanisms
may
underly
pathologies
suggests
both
research
topics
might
benefit
from
complementary
research.
Wolfram
syndrome
1
(WS1)
is
a
rare
genetic
disorder
caused
by
mutations
in
the
WFS1
gene
leading
to
wide
spectrum
of
clinical
dysfunctions,
among
which
blindness,
diabetes,
and
neurological
deficits
are
most
prominent.
encodes
for
endoplasmic
reticulum
(ER)
resident
transmembrane
protein
wolframin
with
multiple
functions
ER
processes.
However,
-dependent
etiopathology
retinal
cells
unknown.
Herein,
we
showed
that
Wfs1
mutant
mice
developed
early
electrophysiological
impairments
followed
marked
visual
loss.
Interestingly,
axons
myelin
disruption
optic
nerve
preceded
degeneration
ganglion
cell
bodies
retina.
Transcriptomics
at
pre-degenerative
stage
revealed
STAT3-dependent
activation
proinflammatory
glial
markers
reduction
homeostatic
pro-survival
factors
glutamine
synthetase
BDNF.
Furthermore,
label-free
comparative
proteomics
identified
significant
monocarboxylate
transport
isoform
(MCT1)
its
partner
basigin
highly
enriched
on
glia
myelin-forming
oligodendrocytes
together
wolframin.
Loss
MCT1
failure
lactate
transfer
from
neuronal
chronic
hypometabolic
state.
Thus,
this
bioenergetic
impairment
occurring
concurrently
both
within
axonal
regions
cells,
selectively
endangering
their
survival
while
impacting
less
other
cells.
This
metabolic
dysfunction
occurs
months
before
frank
RGC
suggesting
an
extended
time-window
intervening
new
therapeutic
strategies
focused
boosting
bioenergetics
WS1.
Cell Death and Disease,
Journal Year:
2023,
Volume and Issue:
14(6)
Published: June 29, 2023
Wolfram
syndrome
(WS)
is
a
rare
neurodegenerative
disorder
encompassing
diabetes
mellitus,
insipidus,
optic
atrophy,
hearing
loss
(HL)
as
well
neurological
disorders.
None
of
the
animal
models
pathology
are
presenting
with
an
early
onset
HL,
impeding
understanding
role
Wolframin
(WFS1),
protein
responsible
for
WS,
in
auditory
pathway.
We
generated
knock-in
mouse,
Wfs1E864K
line,
human
mutation
leading
to
severe
deafness
affected
individuals.
The
homozygous
mice
showed
profound
post-natal
HL
and
vestibular
syndrome,
collapse
endocochlear
potential
(EP)
devastating
alteration
stria
vascularis
neurosensory
epithelium.
mutant
prevented
localization
cell
surface
Na+/K+ATPase
β1
subunit,
key
maintenance
EP.
Overall,
our
data
support
WFS1
EP
vascularis,
via
its
binding
partner,
subunit.
