Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Апрель 6, 2023
Abstract
Mutations
in
GBA1
,
the
gene
encoding
lysosomal
enzyme
β-glucocerebrosidase
(GCase),
which
cause
Gaucher’s
disease,
are
most
frequent
genetic
risk
factor
for
Parkinson’s
disease
(PD).
Here,
we
employ
global
proteomic
and
single-cell
genomic
approaches
stable
cell
lines
as
well
induced
pluripotent
stem
(iPSC)-derived
neurons
midbrain
organoids
to
dissect
mechanisms
underlying
GCase-related
neurodegeneration.
We
demonstrate
that
GCase
can
be
imported
from
cytosol
into
mitochondria
via
recognition
of
internal
mitochondrial
targeting
sequence-like
signals.
In
mitochondria,
promotes
maintenance
complex
I
(CI)
integrity
function.
Furthermore,
interacts
with
quality
control
proteins
HSP60
LONP1.
Disease-associated
mutations
impair
CI
stability
function
enhance
interaction
machinery.
These
findings
reveal
a
role
suggest
defective
activity
energy
metabolism
may
drive
pathogenesis
GCase-linked
Nature,
Год журнала:
2022,
Номер
609(7928), С. 754 - 760
Опубликована: Авг. 8, 2022
Identifying
the
host
genetic
factors
underlying
severe
COVID-19
is
an
emerging
challenge1-5.
Here
we
conducted
a
genome-wide
association
study
(GWAS)
involving
2,393
cases
of
in
cohort
Japanese
individuals
collected
during
initial
waves
pandemic,
with
3,289
unaffected
controls.
We
identified
variant
on
chromosome
5
at
5q35
(rs60200309-A),
close
to
dedicator
cytokinesis
2
gene
(DOCK2),
which
was
associated
patients
less
than
65
years
age.
This
risk
allele
prevalent
East
Asian
but
rare
Europeans,
highlighting
value
studies
non-European
populations.
RNA-sequencing
analysis
473
bulk
peripheral
blood
samples
decreased
expression
DOCK2
these
younger
patients.
suppressed
COVID-19.
Single-cell
(n
=
61
individuals)
cell-type-specific
downregulation
and
COVID-19-specific
decreasing
effect
non-classical
monocytes.
Immunohistochemistry
lung
specimens
from
pneumonia
showed
expression.
Moreover,
inhibition
function
CPYPP
increased
severity
Syrian
hamster
model
SARS-CoV-2
infection,
characterized
by
weight
loss,
oedema,
enhanced
viral
loads,
impaired
macrophage
recruitment
dysregulated
type
I
interferon
responses.
conclude
that
has
important
role
immune
response
infection
development
COVID-19,
could
be
further
explored
as
potential
biomarker
and/or
therapeutic
target.
Science Immunology,
Год журнала:
2023,
Номер
8(83)
Опубликована: Май 12, 2023
Dendritic
cells
(DCs)
mature
in
an
immunogenic
or
tolerogenic
manner
depending
on
the
context
which
antigen
is
perceived,
preserving
balance
between
immunity
and
tolerance.
Whereas
pathways
driving
maturation
response
to
infectious
insults
are
well-characterized,
signals
that
drive
during
homeostasis
still
poorly
understood.
We
found
engulfment
of
apoptotic
triggered
homeostatic
type
1
conventional
DCs
(cDC1s)
within
spleen.
This
process
could
be
mimicked
by
empty,
nonadjuvanted
lipid
nanoparticles
(LNPs),
was
marked
intracellular
accumulation
cholesterol,
highly
specific
cDC1s.
Engulfment
either
cholesterol-rich
LNPs
led
activation
liver
X
receptor
(LXR)
pathway,
promotes
efflux
cellular
repressed
genes
associated
with
maturation.
In
contrast,
simultaneous
engagement
TLR3
mimic
viral
infection
via
administration
poly(I:C)-adjuvanted
LXR
thus
delaying
cholesterol
inducing
promote
T
cell-mediated
immunity.
These
data
demonstrate
conserved
differentially
regulated
versus
cDC1s
suggest
may
approach
for
DC
Nature Methods,
Год журнала:
2023,
Номер
20(12), С. 2034 - 2047
Опубликована: Дек. 1, 2023
Abstract
Ventral
midbrain
dopaminergic
neurons
project
to
the
striatum
as
well
cortex
and
are
involved
in
movement
control
reward-related
cognition.
In
Parkinson’s
disease,
nigrostriatal
degenerate
cause
typical
disease
motor-related
impairments,
while
dysfunction
of
mesocorticolimbic
is
implicated
addiction
neuropsychiatric
disorders.
Study
development
selective
neurodegeneration
human
system,
however,
has
been
limited
due
lack
an
appropriate
model
access
material.
Here,
we
have
developed
a
vitro
that
recapitulates
key
aspects
innervation
cortex.
These
spatially
arranged
ventral
midbrain–striatum–cortical
organoids
(MISCOs)
can
be
used
study
neuron
maturation,
function
with
implications
for
cell
therapy
research.
We
detail
protocols
growing
midbrain,
striatal
cortical
describe
how
they
fuse
linear
manner
when
placed
custom
embedding
molds.
report
formation
functional
long-range
connections
tissues
MISCOs,
show
injected,
midbrain-patterned
progenitors
mature
innervate
tissue.
Using
these
assembloids,
examine
circuit
perturbations
chronic
cocaine
treatment
causes
long-lasting
morphological,
transcriptional
changes
persist
upon
drug
withdrawal.
Thus,
our
method
opens
new
avenues
investigate
transplantation
circuitry
reconstruction
effect
drugs
on
system.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Апрель 6, 2023
Abstract
Mutations
in
GBA1
,
the
gene
encoding
lysosomal
enzyme
β-glucocerebrosidase
(GCase),
which
cause
Gaucher’s
disease,
are
most
frequent
genetic
risk
factor
for
Parkinson’s
disease
(PD).
Here,
we
employ
global
proteomic
and
single-cell
genomic
approaches
stable
cell
lines
as
well
induced
pluripotent
stem
(iPSC)-derived
neurons
midbrain
organoids
to
dissect
mechanisms
underlying
GCase-related
neurodegeneration.
We
demonstrate
that
GCase
can
be
imported
from
cytosol
into
mitochondria
via
recognition
of
internal
mitochondrial
targeting
sequence-like
signals.
In
mitochondria,
promotes
maintenance
complex
I
(CI)
integrity
function.
Furthermore,
interacts
with
quality
control
proteins
HSP60
LONP1.
Disease-associated
mutations
impair
CI
stability
function
enhance
interaction
machinery.
These
findings
reveal
a
role
suggest
defective
activity
energy
metabolism
may
drive
pathogenesis
GCase-linked
