Biomolecules,
Год журнала:
2023,
Номер
13(1), С. 178 - 178
Опубликована: Янв. 15, 2023
Leucine
rich-repeat
kinase
2
(LRRK2)
is
the
most
well-known
etiologic
gene
for
familial
Parkinson’s
disease
(PD).
Its
product
a
large
with
multiple
functional
domains
that
phosphorylates
subset
of
Rab
small
GTPases.
However,
studies
autopsy
cases
LRRK2
mutations
indicate
varied
pathology,
and
molecular
functions
its
relationship
to
PD
pathogenesis
are
largely
unknown.
Recently,
non-autonomous
neurodegeneration
associated
glial
cell
dysfunction
has
attracted
attention
as
possible
mechanism
dopaminergic
neurodegeneration.
Molecular
in
astrocytes
microglia
have
also
suggested
involved
regulation
lysosomal
other
organelle
dynamics
inflammation.
In
this
review,
we
describe
proposed
cells
discuss
involvement
pathomechanisms
PD.
npj Parkinson s Disease,
Год журнала:
2023,
Номер
9(1)
Опубликована: Июль 1, 2023
Almost
2
decades
after
linking
LRRK2
to
Parkinson's
disease,
a
vibrant
research
field
has
developed
around
the
study
of
this
gene
and
its
protein
product.
Recent
studies
have
begun
elucidate
molecular
structures
complexes,
our
understanding
continued
grow,
affirming
decisions
made
years
ago
therapeutically
target
enzyme
for
PD.
Markers
activity,
with
potential
monitor
disease
progression
or
treatment
efficacy,
are
also
under
development.
Interestingly,
there
is
growing
role
outside
central
nervous
system
in
peripheral
tissues
such
as
gut
immune
cells
that
may
contribute
mediated
pathology.
In
perspective,
goal
take
stock
by
discussing
current
state
knowledge
critical
open
questions
field.
FEBS Journal,
Год журнала:
2021,
Номер
289(22), С. 6871 - 6890
Опубликована: Июль 1, 2021
Protein
coding
mutations
in
leucine-rich
repeat
kinase
2
(LRRK2)
cause
familial
Parkinson's
disease
(PD),
and
noncoding
variations
around
the
gene
increase
risk
of
developing
sporadic
PD.
It
is
generally
accepted
that
pathogenic
LRRK2
activity,
resulting
a
toxic
hyperactive
protein
inferred
to
lead
PD
phenotype.
has
long
been
linked
different
membrane
trafficking
events,
but
specific
role
these
events
difficult
resolve.
Recently,
several
papers
have
reported
activation
translocation
cellular
organelles
under
conditions,
which
suggests
may
influence
intracellular
trafficking.
Here,
we
review
what
known
about
at
various
organelle
compartments.
Antioxidants,
Год журнала:
2023,
Номер
12(6), С. 1289 - 1289
Опубликована: Июнь 16, 2023
The
incidence
of
neurological
diseases,
such
as
Parkinson’s
disease,
Alzheimer’s
disease
and
stroke,
is
increasing.
An
increasing
number
studies
have
correlated
these
diseases
with
brain
iron
overload
the
resulting
oxidative
damage.
Brain
deficiency
has
also
been
closely
linked
to
neurodevelopment.
These
disorders
seriously
affect
physical
mental
health
patients
bring
heavy
economic
burdens
families
society.
Therefore,
it
important
maintain
homeostasis
understand
mechanism
affecting
reactive
oxygen
species
(ROS)
balance,
in
neural
damage,
cell
death
and,
ultimately,
leading
development
disease.
Evidence
shown
that
many
therapies
targeting
ROS
imbalances
good
preventive
therapeutic
effects
on
diseases.
This
review
highlights
molecular
mechanisms,
pathogenesis
treatment
strategies
metabolism
Proceedings of the National Academy of Sciences,
Год журнала:
2023,
Номер
120(31)
Опубликована: Июль 24, 2023
Cells
maintain
optimal
levels
of
lysosome
degradative
activity
to
protect
against
pathogens,
clear
waste,
and
generate
nutrients.
Here,
we
show
that
LRRK2,
a
protein
is
tightly
linked
Parkinson's
disease,
negatively
regulates
in
macrophages
microglia
via
transcriptional
mechanism.
Depletion
LRRK2
inhibition
kinase
enhanced
lysosomal
proteolytic
increased
the
expression
multiple
hydrolases.
Conversely,
hyperactive
G2019S
disease
mutant
suppressed
gene
expression.
We
identified
MiT-TFE
transcription
factors
(TFE3,
TFEB,
MITF)
as
mediators
LRRK2-dependent
control
regulated
abundance
nuclear
localization
these
their
depletion
prevented
changes
levels.
These
observations
define
role
for
controlling
support
model
wherein
hyperactivity
may
increase
risk
by
suppressing
activity.
Journal of Cellular Physiology,
Год журнала:
2024,
Номер
239(5)
Опубликована: Март 13, 2024
Abstract
Parkinson's
disease
(PD)
is
the
most
prevalent
neurodegenerative
disorder.
Neuroinflammation
mediated
by
activated
microglia
and
apoptosis
of
dopaminergic
(DA)
neurons
in
midbrain
are
its
primary
pathological
manifestations.
Leucine‐rich
repeat
protein
kinase
2
(LRRK2)
has
been
observed
to
increase
expression
during
neuroinflammation,
however,
effect
LRRK2
on
activation
remains
poorly
understood.
In
this
study,
we
have
established
lipopolysaccharide
(LPS)
treated
BV2
cells
1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine
(MPTP)
models
for
both
vivo
vitro
investigation.
Our
data
reveal
that
can
promote
regulating
ferroptosis
activating
nuclear
factor‐κB.
Inhibition
effectively
suppressed
LPS‐induced
pro‐inflammatory
cytokines
facilitated
secretion
neuroprotective
factors.
Importantly,
co‐overexpressing
glutathione
peroxidase
4
(GPX4),
identified
system
Xc‐GSH–GPX4
pathway
as
a
crucial
component
LRRK2‐mediated
microglial
inflammatory
responses.
Using
culture
supernatant
(MCS)
transfer
model,
found
inhibiting
or
downregulating
prevented
SH‐SY5Y
cell
apoptosis.
Additionally,
abundant
P‐P65
midbrain,
which
was
elevated
MPTP‐induced
PD
along
with
activation.
inhibition
PF‐06447475
attenuated
nigrostriatal
dense
part
MPTP‐treated
mice.
Based
our
findings,
it
evident
plays
critical
role
promoting
neuroinflammatory
response
pathogenesis
pathway.
Taken
together,
highlights
potential
research
therapeutic
value
targeting
regulate
through
ferroptosis.
Biochemical Journal,
Год журнала:
2021,
Номер
478(19), С. 3555 - 3573
Опубликована: Сен. 13, 2021
Much
effort
has
been
devoted
to
the
development
of
selective
inhibitors
LRRK2
as
a
potential
treatment
for
driven
Parkinson's
disease.
In
this
study,
we
first
compare
properties
Type
I
(GSK3357679A
and
MLi-2)
II
(GZD-824,
Rebastinib
Ponatinib)
kinase
that
bind
closed
or
open
conformations
domain,
respectively.
We
show
suppress
phosphorylation
Rab10
Rab12,
key
physiological
substrates
also
promote
mitophagy,
process
suppressed
by
LRRK2.
display
higher
potency
towards
wild-type
compared
with
pathogenic
mutants.
Unexpectedly,
find
inhibitors,
in
contrast
compounds,
fail
induce
dephosphorylation
set
well-studied
biomarker
sites
at
N-terminal
region
LRRK2,
including
Ser935.
These
findings
emphasize
on
are
likely
reporting
vs
conformation
only
which
stabilize
these
sites.
Finally,
demonstrate
LRRK2[A2016T]
mutant
is
resistant
MLi-2
1
inhibitor,
induces
resistance
GZD-824
suggesting
mutation
could
be
exploited
distinguish
off
target
effects
inhibitors.
Our
observations
provide
framework
knowledge
aid
more
