Translational Neurodegeneration,
Journal Year:
2021,
Volume and Issue:
10(1)
Published: Oct. 18, 2021
Abstract
Parkinson’s
disease
(PD)
is
a
common
neurodegenerative
disorder
that
primarily
affects
the
elderly.
While
etiology
of
PD
likely
multifactorial
with
involvement
genetic,
environmental,
aging
and
other
factors,
α-synuclein
(α-syn)
pathology
pivotal
mechanism
underlying
development
PD.
In
recent
years,
astrocytes
have
attracted
considerable
attention
in
field.
Although
perform
variety
physiological
functions
brain,
they
are
mediators
α-syn
toxicity
since
internalize
released
from
damaged
neurons,
this
triggers
an
inflammatory
response,
protein
degradation
dysfunction,
mitochondrial
dysfunction
endoplasmic
reticulum
stress.
Astrocytes
indispensable
coordinators
background
several
genetic
mutations,
including
PARK7,
GBA1,
LRRK2,
ATP13A2,
PINK1,
PRKN
PLA2G6
.
As
most
abundant
glial
cells
functional
can
be
replenished
even
converted
to
neurons.
review,
we
discuss
astrocyte
emphasis
on
modulation
conclude
replenishment
valuable
therapeutic
approach
Molecular Neurodegeneration,
Journal Year:
2022,
Volume and Issue:
17(1)
Published: April 12, 2022
Abstract
Background
Neuronal
uptake
and
subsequent
spread
of
proteopathic
seeds,
such
as
αS
(alpha-synuclein),
Tau,
TDP-43,
contribute
to
neurodegeneration.
The
cellular
machinery
participating
in
this
process
is
poorly
understood.
One
proteinopathy
called
multisystem
(MSP)
associated
with
dominant
mutations
Valosin
Containing
Protein
(VCP).
MSP
patients
have
muscle
neuronal
degeneration
characterized
by
aggregate
pathology
that
can
include
αS,
Tau
TDP-43.
Methods
We
performed
a
fluorescent
cell
sorting
based
genome-wide
CRISPR-Cas9
screen
biosensors.
TDP-43
seeding
activity
under
varied
conditions
was
assessed
using
FRET/Flow
biosensor
cells
or
immunofluorescence
for
phosphorylated
primary
cultured
neurons.
analyzed
vivo
immunostaining
following
intrastriatal
injection
seeds
control
VCP
disease
mutation
carrying
mice.
Results
hundred
fifty-four
genes
were
identified
suppressors
seeding.
suppressor,
when
chemically
genetically
inhibited
increased
This
not
due
an
increase
protein
levels.
MSP-VCP
expression
Intrastriatal
preformed
fibrils
(PFF)
into
VCP-MSP
mice
phospho
compared
Cells
stably
expressing
fluorescently
tagged
C-terminal
fragment
FRET
pairs
(TDP-43
biosensors)
generate
seeded
PFF
but
monomeric
inhibition
mutant
increases
Similarly,
treatment
neurons
PFFs
generates
high
molecular
weight
insoluble
after
5
days.
seed
dependent
phosphorlyated
further
augmented
Conclusion
Using
unbiased
screen,
we
the
multifunctional
AAA
ATPase
suppressor
facilitates
clearance
damaged
lysosomes
via
lysophagy.
propose
VCP’s
surveillance
permeabilized
endosomes
may
protect
against
pathogenic
aggregates.
distinct
species
dictate
pleiotropic
phenotypes
pathologies
MSP.
Journal of Neuroinflammation,
Journal Year:
2023,
Volume and Issue:
20(1)
Published: April 10, 2023
Abstract
Background
Peripheral
inflammation
is
an
important
feature
of
Parkinson’s
disease
(PD).
However,
if
and
how
CNS
pathology
involved
in
the
peripheral
PD
remains
to
be
fully
investigated.
Recently,
existence
meningeal
lymphatics
its
involvement
draining
cerebral
spinal
fluid
(CSF)
cervical
lymph
node
has
been
discovered.
It
known
that
lymphatic
dysfunction
exists
idiopathic
PD.
The
deep
(dCLN)
substantially
contributes
drainage
lymphatics.
In
addition,
one
components,
CSF,
contains
abundant
α-synuclein
(α-syn),
a
protein
critically
pathogenesis
neuroinflammation.
Thus,
we
began
with
exploring
possible
structural
functional
alterations
dCLN
mouse
model
(A53T
mice)
investigated
role
pathological
α-syn
potential
underlying
molecular
mechanisms.
Methods
this
study,
transgenic
mice
(prnp-SNCA*A53T)
which
specifically
overexpressed
A53T
mutant
were
employed
as
animal
model.
Immunofluorescent
Hematoxylin
eosin
staining
used
evaluate
structure
dCLN.
Inflammation
dCLNs
well
bone-marrow-derived
macrophages
(BMDMs)
was
assessed
quantitatively
by
measuring
mRNA
levels
typical
inflammatory
cytokines
(including
IL-1β,
IL-6
TNF-α).
Intra-cisterna
magna
injection,
flow
cytometric
sorting
electrochemiluminescence
immunoassays
applied
investigate
from
CNS.
RNA-seq
Western
blot
explore
mediated
mice.
Results
results
unequivocally
revealed
enlarged
dCLNs,
along
slow
flow,
increased
Oligomeric
drained
CSF
potently
activated
via
endoplasmic
reticulum
(ER)
stress.
Notably,
inhibition
ER
stress
effectively
suppressed
Conclusions
Our
findings
indicate
enlargement
closely
related
macrophage
activation,
induced
oligomeric
α-syn,
therapeutic
target
ameliorate
pathogenesis.
Frontiers in Cell and Developmental Biology,
Journal Year:
2023,
Volume and Issue:
11
Published: April 19, 2023
Endoplasmic
reticulum
(ER)
is
the
largest
membrane-bound
compartment
in
all
cells
and
functions
as
a
key
regulator
protein
biosynthesis,
lipid
metabolism,
calcium
balance.
Mammalian
endoplasmic
has
evolved
with
an
orchestrated
quality
control
system
to
handle
defective
proteins
ensure
homeostasis.
Nevertheless,
accumulation
aggregation
of
misfolded
may
occur
during
pathological
conditions.
The
inability
clear
faulty
aggregates
from
results
development
many
human
disorders.
efforts
comprehensively
understand
network
will
benefit
diagnostics
therapeutics
storage
diseases.
Herein,
we
overview
recent
advances
mammalian
system,
describe
phase
transition
model,
summarize
approaches
monitor
aggregation.
Moreover,
discuss
therapeutic
applications
enhancing
pathways
