bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 31, 2024
Abstract
Background
and
Objectives
TBCK
syndrome
is
a
rare
fatal
pediatric
neurodegenerative
disease
caused
by
biallelic
loss-of-function
mutations
in
the
gene.
Previous
studies
our
lab
others
have
implicated
mTOR,
autophagy,
lysosomes,
intracellular
mRNA
transport,
however
exact
primary
pathologic
mechanism
unknown.
This
gap
has
prevented
development
of
targeted
therapies.
Methods
We
employed
human
neural
progenitor
cell
line
(NPC),
ReNcell
VM,
which
can
differentiate
into
neurons
astrocytes,
to
understand
role
mTORC1
activity
neuronal
autophagy
cellular
mechanisms
pathology.
used
shRNA
technology
knockdown
ReNcells.
Results
These
data
showed
that
loss
did
not
inhibit
neither
NPC
nor
neurons.
Additionally,
analysis
eight
patient-derived
cells
knock
down
HeLa
inhibition
inconsistent
across
different
patients
types.
ReNcells
affected
differentiation
astrocytes.
Specifically,
defects
are
coupled
cycle
increased
death
during
differentiation.
RNAseq
indicated
downregulation
several
neurodevelopmental
pathways.
observed
higher
number
LC3-positive
vesicles
soma
neurites
cells.
Further,
altered
mitochondrial
dynamics
membrane
potential
NPC,
found
partial
rescue
with
fission
inhibitor
mdivi-
1.
Discussion
work
outlines
new
Human
Cell
Model
for
TBCK-related
neurodegeneration
essential
health
inhibitor.
data,
along
illuminate
provide
possible
novel
therapeutic
avenue
patients.
Biochemical Journal,
Год журнала:
2024,
Номер
481(3), С. 119 - 139
Опубликована: Янв. 29, 2024
The
sub-compartmentalization
of
cellular
processes
is
especially
important
in
highly
polarized
cells
such
as
neurons,
their
function
rely
on
complex
morphology.
association
RNAs
to
the
mitochondrial
surface
a
conserved
feature
from
yeast
humans
and
it
regulates
several
aspects
physiology
and,
hence,
functions.
In
mitochondria
are
emerging
platforms
for
RNA
transport
local
protein
translation.
this
review,
we
discuss
how
localization
helps
sustain
function,
can
support
homeostasis,
distal
parts
neuron,
neuronal
activity.
Genes & Development,
Год журнала:
2024,
Номер
38(3-4), С. 98 - 114
Опубликована: Фев. 1, 2024
Cell
diversification
is
at
the
base
of
increasing
multicellular
organism
complexity
in
phylogeny
achieved
during
ontogeny.
However,
there
are
also
functions
common
to
all
cells,
such
as
cell
division,
migration,
translation,
endocytosis,
exocytosis,
etc.
Here
we
revisit
organelles
involved
functions,
reviewing
recent
evidence
unexpected
differences
proteins
these
organelles.
For
instance,
centrosomes
or
mitochondria
differ
significantly
their
protein
composition
different,
sometimes
closely
related,
types.
This
has
relevance
for
development
and
disease.
Particularly
striking
high
amount
diversity
RNA-binding
other
organelles,
which
brings
us
review
RNA
different
suborganelles.
We
include
a
discussion
about
(sub)organelles
nucleolus
ribosomes,
type-specific
been
reported.
propose
here
that
heterogeneity
compartments
represents
novel
mechanism
regulating
diversity.
One
reason
can
be
multiplied
by
contributions
distinct
exemplified
with
moonlighting
function.
The
specialized
still
perform
pan-cellular
but
mode,
discussed
centrosomes,
mitochondria,
vesicles,
These
serve
regulatory
hubs
storage
transport
specific
functionally
important
regulators.
In
this
way,
they
control
differentiation,
plasticity,
survival.
further
examples
highlighting
disease
examine
many
more
types
possible
functional
relevance.
Cellular & Molecular Biology Letters,
Год журнала:
2024,
Номер
29(1)
Опубликована: Апрель 16, 2024
Abstract
Background
The
trafficking
of
cargoes
from
endosomes
to
the
trans
-Golgi
network
requires
numerous
sequential
and
coordinated
steps.
Cargoes
are
sorted
into
endosomal-derived
carriers
that
transported,
tethered,
fused
network.
tethering
step
several
complexes,
including
Golgi-associated
retrograde
protein
complex,
whose
localization
at
is
determined
by
activity
small
GTPases
Arl
Rab
family.
However,
how
complex
recognizes
endosome-derived
will
fuse
with
still
unknown.
Methods
We
studied
using
fluorescent
in
cells
overexpressing
Rab4b
or
after
knocked-down
interfering
RNA
combination
downregulation
subunits
complex.
used
immunofluorescence
image
processing
(Super
Resolution
Radial
Fluctuation
3D
reconstruction)
as
well
biochemical
approaches
characterize
consequences
these
interventions
on
cargo
trafficking.
Results
reported
VPS52
subunit
an
effector
Rab4b.
found
overexpression
wild
type
active
increased
early
endosomal
cation-independent
mannose-6-phosphate
receptor
a
complex-dependent
manner.
Conversely,
inactive
knockdown
attenuated
this
In
absence
Rab4b,
internalized
mannose
6
phosphate
did
not
have
access
VPS52-labeled
structures
look
like
subdomains
and/or
carriers,
subcellular
distribution
Rab4b-independent.
Consequently,
was
blocked
no
longer
had
Conclusion
Our
results
support
controlling
sorting
towards
microdomains,
confers
directional
specificity
for
en
route
Given
importance
endocytic
recycling
cell
homeostasis,
disruption
Rab4b/Golgi-associated
could
serious
pathologies.
Biology,
Год журнала:
2024,
Номер
13(9), С. 746 - 746
Опубликована: Сен. 23, 2024
Mitochondria
are
dynamic
organelles
that
can
adjust
and
respond
to
different
stimuli
within
a
cell.
This
plastic
ability
allows
them
effectively
coordinate
several
cellular
functions
in
cells
becomes
particularly
relevant
highly
complex
such
as
neurons.
An
imbalance
mitochondrial
dynamics
disrupt
function,
leading
abnormal
function
ultimately
range
of
diseases,
including
neurodegenerative
disorders.
Regulation
mRNA
transport
local
translation
inside
neurons
is
crucial
for
maintaining
the
proteome
distal
mitochondria,
which
vital
energy
production
synaptic
function.
A
significant
portion
axonal
transcriptome
dedicated
mRNAs
proteins,
emphasizing
importance
sustaining
areas
far
from
cell
body.
In
neurons,
regulation
encoding
mitochondrial-shaping
proteins
could
be
essential
plasticity
neuronal
health.
The
these
mRNAs,
their
translation,
may
influence
morphology
thereby
affecting
overall
status
responsiveness
synapses.
Comprehending
mitochondria-related
well
its
on
near
synapses
will
help
better
understand
physiology
neurological
diseases
where
dysfunction
impaired
play
central
role.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 31, 2024
Abstract
Background
and
Objectives
TBCK
syndrome
is
a
rare
fatal
pediatric
neurodegenerative
disease
caused
by
biallelic
loss-of-function
mutations
in
the
gene.
Previous
studies
our
lab
others
have
implicated
mTOR,
autophagy,
lysosomes,
intracellular
mRNA
transport,
however
exact
primary
pathologic
mechanism
unknown.
This
gap
has
prevented
development
of
targeted
therapies.
Methods
We
employed
human
neural
progenitor
cell
line
(NPC),
ReNcell
VM,
which
can
differentiate
into
neurons
astrocytes,
to
understand
role
mTORC1
activity
neuronal
autophagy
cellular
mechanisms
pathology.
used
shRNA
technology
knockdown
ReNcells.
Results
These
data
showed
that
loss
did
not
inhibit
neither
NPC
nor
neurons.
Additionally,
analysis
eight
patient-derived
cells
knock
down
HeLa
inhibition
inconsistent
across
different
patients
types.
ReNcells
affected
differentiation
astrocytes.
Specifically,
defects
are
coupled
cycle
increased
death
during
differentiation.
RNAseq
indicated
downregulation
several
neurodevelopmental
pathways.
observed
higher
number
LC3-positive
vesicles
soma
neurites
cells.
Further,
altered
mitochondrial
dynamics
membrane
potential
NPC,
found
partial
rescue
with
fission
inhibitor
mdivi-
1.
Discussion
work
outlines
new
Human
Cell
Model
for
TBCK-related
neurodegeneration
essential
health
inhibitor.
data,
along
illuminate
provide
possible
novel
therapeutic
avenue
patients.
