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
Annual Review of Biochemistry,
Год журнала:
2024,
Номер
93(1), С. 261 - 287
Опубликована: Апрель 15, 2024
Activating
mutations
in
leucine-rich
repeat
kinase
2
(LRRK2)
represent
the
most
common
cause
of
monogenic
Parkinson's
disease.
LRRK2
is
a
large
multidomain
protein
that
phosphorylates
specific
subset
∼65
human
Rab
GTPases,
which
are
master
regulators
secretory
and
endocytic
pathways.
After
phosphorylation
by
LRRK2,
Rabs
lose
capacity
to
bind
cognate
effector
proteins
guanine
nucleotide
exchange
factors.
Moreover,
phosphorylated
cannot
interact
with
their
prenyl-binding
retrieval
(also
known
as
dissociation
inhibitors)
and,
thus,
they
become
trapped
on
membrane
surfaces.
Instead,
gain
phospho-Rab-specific
proteins,
such
RILPL1,
resulting
pathological
consequences.
also
act
upstream
controlling
its
activation
recruitment
onto
membranes.
signaling
counteracted
phosphoprotein
phosphatase
PPM1H,
selectively
dephosphorylates
phospho-Rab
proteins.
We
present
here
our
current
understanding
structure,
biochemical
properties,
cell
biology
related
paralog
LRRK1
discuss
how
this
information
guides
generation
inhibitors
for
potential
benefit
patients.
Cells,
Год журнала:
2024,
Номер
13(1), С. 103 - 103
Опубликована: Янв. 4, 2024
Autophagy
is
a
major
degradative
pathway
that
plays
key
role
in
sustaining
cell
homeostasis,
integrity,
and
physiological
functions.
Macroautophagy,
which
ensures
the
clearance
of
cytoplasmic
components
engulfed
double-membrane
autophagosome
fuses
with
lysosomes,
orchestrated
by
complex
cascade
events.
has
particularly
strong
impact
on
nervous
system,
mutations
core
cause
numerous
neurological
diseases.
We
first
review
regulation
autophagy,
from
biogenesis
to
lysosomal
degradation
associated
neurodevelopmental/neurodegenerative
disorders.
then
describe
how
this
process
specifically
regulated
axon
somatodendritic
compartment
it
altered
In
particular,
we
present
neuronal
specificities
spatial
control
biogenesis,
close
relationship
maturation
axonal
transport,
synaptic
activity.
Finally,
discuss
functions
autophagy
during
development
adulthood.
The Journal of Cell Biology,
Год журнала:
2023,
Номер
222(12)
Опубликована: Ноя. 1, 2023
Neuronal
autophagosomes
form
and
engulf
cargos
at
presynaptic
sites
in
the
axon
are
then
transported
to
soma
recycle
their
cargo.
Autophagic
vacuoles
(AVs)
mature
en
route
via
fusion
with
lysosomes
become
degradatively
competent
organelles;
transport
is
driven
by
microtubule
motor
protein
cytoplasmic
dynein,
activity
regulated
a
sequential
series
of
adaptors.
Using
lysate-based
single-molecule
motility
assays
live-cell
imaging
primary
neurons,
we
show
that
JNK-interacting
proteins
3
(JIP3)
4
(JIP4)
activating
adaptors
for
dynein
on
small
GTPases
ARF6
RAB10.
GTP-bound
promotes
formation
JIP3/4–dynein–dynactin
complex.
Either
knockdown
or
overexpression
RAB10
stalls
transport,
suggesting
this
GTPase
also
required
coordinate
opposing
activities
bound
kinesin
motors.
These
findings
highlight
complex
coordination
regulation
during
organelle
neurons.
Journal of Neural Transmission,
Год журнала:
2024,
Номер
131(6), С. 663 - 674
Опубликована: Апрель 13, 2024
Parkinson's
disease
(PD)
is
a
neurodegenerative
disorder
characterized
by
progressive
degeneration
of
dopaminergic
neurons
in
the
substantia
nigra
and
other
brain
regions.
A
key
pathological
feature
PD
abnormal
accumulation
α-synuclein
protein
within
affected
neurons,
manifesting
as
Lewy
bodies
neurites.
Despite
extensive
research
efforts
spanning
several
decades,
underlying
mechanisms
disease-modifying
therapies
remain
elusive.
This
review
provides
an
overview
current
trends
basic
on
PD.
Initially,
it
discusses
involvement
mitochondrial
dysfunction
pathogenesis
PD,
followed
insights
into
role
lysosomal
disruptions
vesicular
transport
system.
Additionally,
delves
physiological
roles
α-synuclein,
crucial
associated
with
pathophysiology.
Overall,
purpose
this
to
comprehend
state
elucidating
intricate
outline
future
directions
understanding
disease.
The Journal of Cell Biology,
Год журнала:
2024,
Номер
223(6)
Опубликована: Март 21, 2024
Gain-of-function
mutations
in
the
LRRK2
gene
cause
Parkinson’s
disease
(PD),
characterized
by
debilitating
motor
and
non-motor
symptoms.
Increased
phosphorylation
of
a
subset
RAB
GTPases
is
implicated
PD
pathogenesis.
We
find
that
increased
RAB3A,
cardinal
synaptic
vesicle
precursor
(SVP)
protein,
disrupts
anterograde
axonal
transport
SVPs
iPSC-derived
human
neurons
(iNeurons)
expressing
hyperactive
LRRK2-p.R1441H.
Knockout
opposing
protein
phosphatase
1H
(PPM1H)
iNeurons
phenocopies
this
effect.
In
these
models,
compartmental
distribution
proteins
altered;
synaptophysin
synaptobrevin-2
become
sequestered
neuronal
soma
with
decreased
delivery
to
presynaptic
sites
along
axon.
RAB3A
binding
adaptor
MADD,
potentially
preventing
formation
RAB3A–MADD-KIF1A/1Bβ
complex
driving
SVP
transport.
hyperphosphorylation
also
interactions
RAB3GAP
RAB-GDI1.
Our
results
reveal
mechanism
which
pathogenic
may
contribute
altered
homeostasis
associated
characteristic
cognitive
manifestations
PD.
Proceedings of the National Academy of Sciences,
Год журнала:
2025,
Номер
122(5)
Опубликована: Янв. 28, 2025
Mutations
in
Leucine-rich
repeat
kinase
2
(LRRK2)
and
PTEN-induced
1
(PINK1)
are
associated
with
familial
Parkinson’s
disease
(PD).
LRRK2
phosphorylates
Rab
guanosine
triphosphatase
(GTPases)
within
the
Switch
II
domain
while
PINK1
directly
Parkin
ubiquitin
(Ub)
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
Ub
phosphorylation.
In
addition,
observe
pool
Rab-specific,
protein
phosphatase
family
member
1H
phosphatase,
is
transcriptionally
up-regulated
recruited
to
damaged
mitochondria,
independent
or
activity.
Parallel
signaling
pathways
supported
by
assessment
motor
behavioral
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
transcription.
This
exacerbated
double-mutant
mice.
Overall,
our
analysis
indicates
activation
and/or
function
along
parallel
impair
ciliogenesis,
suggesting
convergent
mechanism
toward
PD.
Our
data
suggest
reversal
defects
downstream
offers
common
therapeutic
strategy
for
PD
patients,
whereas
inhibitors
currently
clinical
trials
unlikely
benefit
patients.
