bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 17, 2024
ABSTRACT
Parkinson
disease-causing
mutations
in
the
LRRK2
gene
hyperactivate
kinase
activity,
leading
to
increased
phosphorylation
of
a
subset
RAB
GTPases,
which
are
master
regulators
intracellular
trafficking.
In
neurons,
processive
retrograde
transport
autophagosomes
is
essential
for
autophagosome
maturation
and
effective
degradation
autophagosomal
cargo
axon.
We
found
that
knockout
LRRK2-counteracting
phosphatase
PPM1H
resulted
dose-dependent
disruption
axonal
autophagosomes,
impaired
alpha-synuclein
(aSyn),
key
protein
disease
pathophysiology.
Defective
aSyn
also
correlated
with
aggregation
primary
neurons
exposed
preformed
fibrils
aSyn,
an
effect
was
dependent
on
activity.
Thus,
our
results
link
LRRK2-mediated
hyperphosphorylation
pathology
further
establish
role
autophagy
Brain Sciences,
Год журнала:
2025,
Номер
15(4), С. 407 - 407
Опубликована: Апрель 17, 2025
Leucine-rich
repeat
kinase
2
(LRRK2)
is
a
multifunctional
protein
intricately
involved
in
the
pathogeneses
of
various
neurodegenerative
diseases,
particularly
Parkinson's
disease
(PD).
LRRK2
plays
pivotal
role
mitochondrial
function
and
cellular
senescence
by
regulating
key
processes
such
as
autophagy,
oxidative
stress,
aggregation.
also
associated
with
ciliogenesis
neuronal
development.
In
addition,
has
been
implicated
putative
mediator
neuroinflammation
via
promoting
reactivation
microglia
influencing
cytokine
production,
factor
that
may
have
therapeutic
implications.
Furthermore,
mutations
found
to
impact
production
neurotrophic
factors
astrocytes,
star-shaped
glial
cells
central
nervous
system,
thereby
affecting
health
contributing
pathology
diseases
like
PD.
The
multifaceted
roles
senescence,
interaction
LRS,
neuroinflammation,
maintenance
mitochondria,
astrocyte
highlight
its
significance
target
for
disorders.
Journal of Molecular Biology,
Год журнала:
2025,
Номер
unknown, С. 169161 - 169161
Опубликована: Апрель 1, 2025
Mitochondrial
quality
control
is
instrumental
in
regulating
neuronal
health
and
survival.
The
receptor-mediated
clearance
of
damaged
mitochondria
by
autophagy,
known
as
mitophagy,
plays
a
key
role
controlling
mitochondrial
homeostasis.
Mutations
genes
that
regulate
mitophagy
are
causative
for
familial
forms
neurological
disorders
including
Parkinson's
disease
(PD)
Amyotrophic
lateral
sclerosis(ALS).
PINK1/Parkin-dependent
the
best
studied
pathway,
while
more
recent
work
has
brought
to
light
additional
mechanisms
operate
either
parallel
or
independent
PINK1/Parkin
mitophagy.
Here,
we
discuss
our
current
understanding
operating
neurons
govern
We
also
summarize
progress
links
between
mitophagic
dysfunction
neurodegeneration
highlight
potential
therapeutic
interventions
maintain
function.
Frontiers in Cell and Developmental Biology,
Год журнала:
2025,
Номер
13
Опубликована: Апрель 30, 2025
In
humans,
variants
in
the
LRRK2
gene
are
most
prevalent
risk
factors
for
Parkinson's
disease
(PD).
Whereas
studies
model
organisms
have
long
indicated
that
orthologs
of
wild-type
LRRK
proteins
protect
against
neurodegeneration,
newer
findings
indicate
they
also
neurodevelopmental
defects.
This
normal
role
can
be
disrupted
by
either
gain-of-function
(GOF)
or
loss-of-function
(LOF)
mutations,
leading
to
neurodegeneration
and
Here,
we
review
roles
their
these
processes,
with
a
focus
on
autophagy
as
common
factor
may
mediate
both
roles.
We
highlight
potential
experiments
vertebrate
invertebrate
systems
synergistically
inform
our
understanding
protecting
neurological
disorders.
The Journal of Physiological Sciences,
Год журнала:
2023,
Номер
73(1)
Опубликована: Ноя. 15, 2023
Physiological
roles
of
Cl-,
a
major
anion
in
the
body,
are
not
well
known
compared
with
those
cations.
This
review
article
introduces:
(1)
Cl-
bodily
and
cellular
functions;
(2)
range
cytosolic
concentration
([Cl-]c);
(3)
whether
[Cl-]c
could
change
cell
volume
under
an
isosmotic
condition;
(4)
conditions
where
multiple
transporters
channels
contribute
to
influx
efflux
state;
(5)
be
large
enough
act
as
signals;
(6)
effects
on
cytoskeletal
tubulin
polymerization
through
inhibition
GTPase
activity
polymerization-dependent
biological
activity;
(7)
proliferation;
(8)
Cl--regulatory
mechanisms
ciliary
motility;
(9)
sweet/umami
taste
receptors;
(10)
with-no-lysine
kinase
(WNK);
(11)
regulation
epithelial
Na+
transport;
(12)
relationship
between
H+
body
functions.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Янв. 29, 2023
Neuronal
autophagosomes,
"self-eating"
degradative
organelles,
form
at
presynaptic
sites
in
the
distal
axon
and
are
transported
to
soma
recycle
their
cargo.
During
transit,
autophagic
vacuoles
(AVs)
mature
through
fusion
with
lysosomes
acquire
enzymes
necessary
breakdown
AV
transport
is
driven
primarily
by
microtubule
motor
cytoplasmic
dynein
concert
dynactin
a
series
of
activating
adaptors
that
change
depending
on
organelle
maturation
state.
The
AVs
regulated
scaffolding
proteins
JIP3
JIP4,
both
which
activate
motility
vitro.
also
ARF6
GTP-dependent
fashion.
While
GTP-bound
promotes
formation
JIP3/4-dynein-dynactin
complex,
RAB10
competes
activity
this
complex
increasing
kinesin
recruitment
axonal
lysosomes.
These
interactions
highlight
coordination
motors
regulating
neurons.
Journal of Cell Science,
Год журнала:
2024,
Номер
137(3)
Опубликована: Фев. 1, 2024
ABSTRACT
Most
of
the
vesicular
transport
pathways
inside
cell
are
facilitated
by
molecular
motors
that
move
along
cytoskeletal
networks.
Autophagy
is
a
well-explored
catabolic
pathway
initiated
formation
an
isolation
membrane
known
as
phagophore,
which
expands
to
form
double-membraned
structure
captures
its
cargo
and
eventually
moves
towards
lysosomes
for
fusion.
Molecular
elements
have
been
suggested
participate
at
different
stages
process
autophagic
vesicles
tracks.
Dynein
kinesins
govern
autophagosome
trafficking
on
microtubules
through
sequential
recruitment
their
effector
proteins,
post-translational
modifications
interactions
with
LC3-interacting
regions
(LIRs).
In
contrast,
myosins
actin-based
in
various
flux,
well
selective
autophagy
pathways.
However,
several
outstanding
questions
remain
regard
how
dominance
particular
motor
protein
over
another
controlled,
mechanisms
underlie
specific
disease
variants
proteins.
this
Review,
we
aim
provide
overview
role
highlight
dysregulation
diseases,
such
neurodegenerative
disorders
pathogenic
infections,
ageing.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Апрель 3, 2024
ABSTRACT
Lysosomes
are
dynamic
cellular
structures
that
adaptively
remodel
their
membrane
in
response
to
stimuli,
including
damage.
We
previously
uncovered
a
process
we
term
LYTL
(LYsosomal
Tubulation/sorting
driven
by
Leucine-Rich
Repeat
Kinase
2
[LRRK2]),
wherein
damaged
lysosomes
generate
tubules
sorted
into
mobile
vesicles.
is
orchestrated
the
Parkinson’s
disease-associated
kinase
LRRK2
recruits
motor
adaptor
protein
and
RHD
family
member
JIP4
via
phosphorylated
RAB
proteins.
To
identify
new
players
involved
LYTL,
performed
unbiased
proteomics
on
isolated
after
inhibition.
Our
results
demonstrate
there
recruitment
of
RILPL1
ruptured
activity
promote
phosphorylation
proteins
at
lysosomal
surface.
RILPL1,
which
also
family,
enhances
clustering
LRRK2-positive
perinuclear
area
causes
retraction
tubules,
contrast
promotes
tubule
extension.
Mechanistically,
binds
p150
Glued
,
dynactin
subunit,
facilitating
transport
minus
end
microtubules.
Further
characterization
tubulation
revealed
move
along
tyrosinated
microtubules,
with
tubulin
tyrosination
proving
essential
for
elongation.
In
summary,
our
findings
emphasize
regulation
two
distinct
pRAB
effectors,
serving
as
opposing
proteins:
JIP4,
promoting
kinesin,
through
dynein/dynactin.
infer
processes
metastable
deformation
facilitates
events.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 11, 2024
ABSTRACT
Mutations
in
LRRK2
and
PINK1
are
associated
with
familial
Parkinson’s
disease
(PD).
phosphorylates
Rab
GTPases
within
the
Switch
II
domain
whilst
directly
Parkin
ubiquitin
indirectly
induces
phosphorylation
of
a
subset
GTPases.
Herein
we
have
crossed
[R1441C]
mutant
knock-in
mice
knock-out
(KO)
report
that
loss
does
not
impact
endogenous
LRRK2-mediated
nor
do
see
significant
effect
on
PINK1-mediated
phosphorylation.
In
addition,
observe
pool
Rab-specific,
PPM1H
phosphatase,
is
transcriptionally
up-regulated
recruited
to
damaged
mitochondria,
independent
or
activity.
Parallel
signalling
pathways
supported
by
assessment
motor
behavioural
studies
show
no
evidence
genetic
interaction
mouse
lines.
Previously
showed
cilia
R1441C
herein
KO
exhibit
ciliogenesis
defect
striatal
cholinergic
interneurons
astrocytes
interferes
Hedgehog
induction
glial
derived-neurotrophic
factor
(GDNF)
transcription.
This
exacerbated
double
mice.
Overall,
our
analysis
indicates
activation
and/or
function
along
parallel
impair
ciliogenesis,
suggesting
convergent
mechanism
towards
PD.
Our
data
suggests
reversal
defects
downstream
offers
common
therapeutic
strategy
for
PD
patients
whereas
inhibitors
currently
clinical
trials
unlikely
benefit
patients.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 19, 2024
Leucine-rich
repeat
kinase
2
(LRRK2)
phosphorylates
a
subset
of
RAB
GTPases,
and
the
phosphorylation
levels
are
elevated
by
Parkinson's
disease
(PD)-linked
mutations
LRRK2.
However,
precise
function
specific
GTPase
targeted
LRRK2
signaling
in
brain
remains
to
be
elucidated.
Here,
we
identify
RAB12
as
robust
substrate
mouse
brains
through
phosphoproteomics
profiling
solve
structure
RAB12-LRRK2
protein
complex
Cryo-EM
analysis.
Mechanistically,
cooperates
with
inhibit
primary
ciliogenesis
regulate
centrosome
homeostasis
astrocytes
enhancing
RAB10
recruiting
Rab
interacting
lysosomal
like
1
(RILPL1),
while
functions
require
direct
interaction
activity.
Furthermore,
ciliary
deficits
alteration
caused
PD-linked
LRRK2-G2019S
mutation
prevented
deletion