bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 7, 2024
ABSTRACT
Autophagic
dysfunction
is
a
hallmark
of
neurodegenerative
disease,
leaving
neurons
vulnerable
to
the
accumulation
damaged
organelles
and
proteins.
However,
late
onset
diseases
suggests
that
compensatory
quality
control
mechanisms
may
be
engaged
delay
deleterious
effects
induced
by
compromised
autophagy.
Neurons
expressing
common
familial
Parkinson’s
disease
(PD)-associated
mutations
in
LRRK2
kinase
exhibit
defective
Here,
we
demonstrate
both
primary
murine
human
iPSC-derived
harboring
pathogenic
upregulate
secretion
extracellular
vesicles.
We
used
unbiased
proteomics
characterize
secretome
G2019S
found
autophagic
cargos
including
mitochondrial
proteins
were
enriched.
Based
on
these
observations,
hypothesized
autophagosomes
are
rerouted
toward
when
cell-autonomous
degradation
compromised,
likely
mediate
clearance
undegraded
cellular
waste.
Immunoblotting
confirmed
release
immunocytochemistry
demonstrated
secretory
autophagy
was
upregulated
neurons.
also
exosomes
containing
miRNAs.
Live-cell
imaging
this
upregulation
exosomal
dependent
hyperactive
activity,
while
pharmacological
experiments
indicate
staves
off
apoptosis.
Finally,
show
markers
vesicle
populations
plasma
from
mice
LRRK2.
In
sum,
find
secreted
exosomes,
waste
disposal
transcellular
communication,
respectively.
propose
increased
contributes
maintenance
homeostasis,
delaying
progression
over
short
term
potentially
contributing
neuroinflammation
longer
term.
SIGNIFICANCE
A
feature
many
dysfunction,
resulting
detrimental
neuronal
health.
The
diseases,
however,
alternative
degeneration.
Disease-causing
mutation
two
populations.
First,
observe
expulsion
disposal.
Second,
facilitate
communication.
Thus,
increases
exosome
homeostatic
response
undergoing
chronic
stress.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 19, 2025
Abstract
While
electrical
activity
in
neurons
has
been
extensively
studied,
the
transport
and
distribution
of
adenosine
triphosphate
(ATP),
primary
cellular
energy
carrier,
remain
less
understood,
particularly
relation
to
metabolic
processes
axons.
ATP
is
primarily
generated
mitochondria
consumed
at
synapses,
sites
demand.
Even
healthy
axons,
approximately
half
synaptic
boutons
lack
stationary
mitochondria,
raising
questions
about
between
with
without
mitochondrial
production.
This
study
addresses
two
key
questions:
role
spontaneous
neuronal
firing
maintaining
levels
during
periods
low
demand
ability
a
single
bouton
donated
mitochondrion
supply
neighboring
lacking
mitochondria.
Using
computational
simulations,
examines
under
various
patterns
distributions,
incorporating
factors
such
as
quiescent
periods,
duty
cycles,
diffusivity.
Spontaneous
stabilizes
demand,
preventing
reactive
oxygen
species
(ROS)
release
from
Simulations
reveal
that
damaged
by
neurodegeneration,
containing
can
support
multiple
empty
boutons.
However,
number
increases,
concentration
declines,
potentially
falling
below
critical
threshold
required
for
transmission.
Nomenclature
0
kinetic
constant
characterizing
rate
consumption
A
c
cross-sectional
area
axon
C
per
unit
length
typical
value
min
minimum
sustain
transmission
cycle
D
diffusivity
cytosol
f
frequency
which
neuron
fires
active
phase
i
action
potentials
occur
total
propagate
down
plus
were
missed
L
distance
m
production
mass
tissue
N
CV
t
time
x
position
along
half-length
Greek
symbols
γ
percentage
volume
occupied
δ
width
an
axonal
varicosity
ϖ
individual
Λ
homeostatic
portion
expended
on
maintenance
Cellular and Molecular Life Sciences,
Journal Year:
2025,
Volume and Issue:
82(1)
Published: Feb. 2, 2025
Neurodegenerative
diseases
(NDs)
are
a
group
of
neurological
disorders
characterized
by
the
progressive
loss
selected
neurons.
Alzheimer's
disease
(AD)
and
Parkinson's
(PD)
most
common
NDs.
Pathologically,
NDs
failure
neural
interactions
aberrant
protein
fibril
aggregation
deposition,
which
lead
to
neuron
cognitive
behavioral
impairments.
Great
efforts
have
been
made
delineate
underlying
mechanism
However,
very
first
trigger
these
state
illness
still
vague.
Existing
therapeutic
strategies
can
relieve
symptoms
but
cannot
cure
diseases.
The
human
immune
system
is
complex
intricate
network
comprising
various
components
that
work
together
protect
body
against
pathogens
maintain
overall
health.
They
be
broadly
divided
into
two
main
types:
innate
immunity,
line
defense
pathogens,
acts
nonspecifically,
adaptive
follows
process
more
specifically
targeted.
significance
brain
immunity
in
maintaining
homeostatic
environment
brain,
its
direct
implications
NDs,
has
increasingly
come
focus.
Some
beneficial
regulatory
effects,
whereas
others
may
detrimental
effects
on
interplay
mechanisms
remain
an
area
active
research.
This
review
focuses
both
AD
PD,
offering
comprehensive
understanding
initiation
regulation
as
well
between
influencing
progression
Ageing and Neurodegenerative Diseases,
Journal Year:
2025,
Volume and Issue:
5(1)
Published: Feb. 22, 2025
Aging
is
a
major
risk
factor
for
different
neurodegenerative
diseases
(NDDs),
including
Parkinson’s
disease
(PD).
In
PD,
one
of
the
key
neuropathological
features
cytoplasmic
protein
aggregation,
named
Lewy
bodies
(LBs)
in
cell
body,
and
neurites
(LNs)
neuronal
processes
terminals.
The
α-synuclein
(α-syn)
has
been
found
to
be
component
LBs
LNs,
considered
play
central
role
their
formation.
α-Syn
also
increases
healthy
aging
conditions.
Evidence
shown
that
promotes
α-syn
pathological
aggregation
propagation
and,
therefore,
may
induce
aggravate
PD
pathogenesis.
Here,
we
aim
highlight
recent
advances
age-related
prion-like
discuss
subsequent
consequences
functions.
Biomolecules,
Journal Year:
2025,
Volume and Issue:
15(3), P. 379 - 379
Published: March 5, 2025
Peak1-related,
kinase-activating
pseudokinase
1
(PRAG1),
a
member
of
the
pseudopodium-enriched
atypical
kinase
(PEAK)
family
pseudokinases,
has
been
reported
to
play
role
in
regulating
cell
morphology.
However,
molecular
mechanism
for
this
function
remains
elusive.
In
study,
we
demonstrate
that
PRAG1
forms
dynamic
condensates
cells
mediated
by
its
αN
and
αJ
helices.
Importantly,
found
functioned
mediating
contraction,
while
condensate-formation-deficient
mutants
lost
function.
Remarkably,
formation
spherical
appears
be
common
phenomenon
diverse
stress
models,
as
well
dopaminergic
(DA)
neurons
derived
from
Parkinson’s
disease
patient.
Our
findings
reveal
novel
through
which
drives
contraction
suggest
potential
link
between
aberrant
phase
separation
stress-induced
contraction.
condensation
under
stress.
Exploration of neuroscience,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 11, 2025
Purinergic
signaling,
mediated
by
ATP
and
adenosine
receptors,
plays
a
crucial
role
in
cellular
communication
homeostasis
within
the
central
nervous
system
(CNS),
particularly
regulating
synaptic
activity,
glial
cell
functions,
neuroplasticity.
Glial
cells,
including
astrocytes
microglia,
contribute
to
both
short-term
processes,
such
as
neurotransmission
neuroinflammation,
long-term
remodeling,
tissue
repair,
behavioral
adaptation.
Dysregulation
of
purinergic
signaling
these
cells
has
been
implicated
pathogenesis
various
neurodegenerative
neuropsychiatric
disorders.
This
article
explores
evolving
concept
synapse,
highlighting
active
modulation
emphasizing
significance
function
responses
conditions
injury
neurotoxicity.
Specifically,
it
examines
roles
receptors—such
P2X4,
P2X7,
P2Y1,
P2Y12—in
mediating
key
astrocytic
microglial
phagocytosis,
plasticity,
neuronal
damage.
Furthermore,
discusses
involvement
receptors
neurological
disorders
epilepsy,
Alzheimer’s
disease,
Parkinson’s
multiple
sclerosis,
ischemic
stroke,
Rett
syndrome,
autism
spectrum
disorder,
well
potential
therapeutic
strategies
targeting
mitigate
inflammation,
promote
improve
clinical
outcomes.
