medRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2023,
Volume and Issue:
unknown
Published: June 22, 2023
Abstract
Background
Recent
studies
have
advanced
our
understanding
of
the
genetic
drivers
Parkinson’s
Disease
(PD).
Rare
variants
in
more
than
20
genes
are
considered
causal
for
PD,
and
latest
PD
GWAS
study
identified
90
independent
risk
loci.
However,
there
remains
a
gap
genetics
outside
European
populations
which
vast
majority
these
were
focused.
Objectives
To
identify
factors
South
Asian
population.
Methods
674
subjects
predominantly
with
age
onset
≤
50
years
(encompassing
juvenile,
young,
or
early-onset
PD)
recruited
from
10
specialty
movement
disorder
centers
across
India
over
2-year
period.
1,376
control
selected
reference
population
GenomeAsia,
Phase
2.
We
performed
various
case-only
case-control
analyses
diagnosis
onset.
Results
A
genome-wide
significant
signal
was
SNCA
region,
strongly
colocalizing
region
GWAS.
cases
pathogenic
mutations
exhibited,
on
average,
lower
polygenic
scores
lacking
any
gene
mutations.
Gene
burden
rare,
predicted
deleterious
BSN
,
encoding
presynaptic
protein
Bassoon
that
has
been
previously
associated
neurodegenerative
disease.
Conclusions
This
constitutes
largest
investigation
to
date.
Future
work
should
seek
expand
sample
numbers
this
enable
improved
statistical
power
detect
understudied
group.
Autophagy,
Journal Year:
2023,
Volume and Issue:
20(4), P. 883 - 901
Published: Oct. 26, 2023
In
neurons,
autophagosome
biogenesis
occurs
mainly
in
distal
axons,
followed
by
maturation
during
retrograde
transport.
Autophagosomal
growth
depends
on
the
supply
of
membrane
lipids
which
requires
small
vesicles
containing
ATG9,
a
lipid
scramblase
essential
for
macroautophagy/autophagy.
Here,
we
show
that
ATG9-containing
are
enriched
synapses
and
resemble
synaptic
size
density.
The
proteome
immuno-isolated
from
nerve
terminals
showed
conspicuously
low
levels
trafficking
proteins
except
AP2-complex
some
enzymes
involved
endosomal
phosphatidylinositol
metabolism.
Super
resolution
microscopy
isolated
revealed
represent
distinct
vesicle
population
with
limited
overlap
not
only
but
also
other
membranes
secretory
pathway,
uncovering
surprising
heterogeneity
their
composition.
Our
results
compatible
view
function
as
shuttles
scavenge
various
intracellular
to
support
biogenesis.
Biomedicines,
Journal Year:
2023,
Volume and Issue:
11(2), P. 289 - 289
Published: Jan. 20, 2023
Animal
models
of
psychopathologies
are
exceptional
interest
for
neurobiologists
because
these
allow
us
to
clarify
molecular
mechanisms
underlying
the
pathologies.
One
such
model
is
inbred
BTBR
strain
mice,
which
characterized
by
behavioral,
neuroanatomical,
and
physiological
hallmarks
schizophrenia
(SCZ)
autism
spectrum
disorders
(ASDs).
Despite
active
use
mice
as
a
object,
understanding
features
this
that
cause
observed
behavioral
phenotype
remains
insufficient.
Here,
we
analyzed
recently
published
data
from
independent
transcriptomic
proteomic
studies
on
hippocampal
corticostriatal
samples
search
most
consistent
aberrations
in
gene
or
protein
expression.
Next,
compared
reproducible
signatures
with
postmortem
ASD
SCZ
patients.
Taken
together,
helped
elucidate
brain-region-specific
abnormalities
well
their
relevance
anomalies
seen
ASDs
humans.
Neuron,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 1, 2025
Neurons
are
long-lived
postmitotic
cells
that
capitalize
on
autophagy
to
remove
toxic
or
defective
proteins
and
organelles
maintain
neurotransmission
the
integrity
of
their
functional
proteome.
Mutations
in
genes
cause
congenital
diseases,
sharing
prominent
brain
dysfunctions
including
epilepsy,
intellectual
disability,
neurodegeneration.
Ablation
core
neurons
glia
disrupts
normal
behavior,
leading
motor
deficits,
memory
impairment,
altered
sociability,
which
associated
with
defects
synapse
maturation,
plasticity,
neurotransmitter
release.
In
spite
importance
for
physiology,
substrates
neuronal
mechanisms
by
affect
synaptic
function
health
disease
remain
controversial.
Here,
we
summarize
current
state
knowledge
autophagy,
address
existing
controversies
inconsistencies
field,
provide
a
roadmap
future
research
role
control
function.
Cell Death Discovery,
Journal Year:
2023,
Volume and Issue:
9(1)
Published: Oct. 14, 2023
Abstract
Alzheimer’s
disease
is
the
most
common
age-associated
neurodegenerative
disorder
and
frequent
form
of
dementia
in
our
society.
Aging
a
complex
biological
process
concurrently
shaped
by
genetic,
dietary
environmental
factors
natural
compounds
are
emerging
for
their
beneficial
effects
against
age-related
disorders.
Besides
antioxidant
activity
often
described
simple
model
organisms,
molecular
mechanisms
underlying
different
remain
however
largely
unknown.
In
present
study,
we
exploit
nematode
Caenorhabditis
elegans
as
widely
established
aging
studies,
to
test
vivo
focused
on
mechanistic
aspects
one
them,
quercetin,
using
complementary
systems
assays.
We
show
that
quercetin
has
evolutionarily
conserved
(AD)
pathology:
it
prevents
Amyloid
beta
(Aβ)-induced
detrimental
C.
AD
models
reduces
Aβ-secretion
mammalian
cells.
Mechanistically,
found
mediated
autophagy-dependent
reduced
expression
Abl
tyrosine
kinase.
turn,
autophagy
required
upon
suppression
mediate
quercetin’s
protective
Aβ
toxicity.
Our
data
support
power
an
investigate
therapeutic
options
AD.
The Journal of Cell Biology,
Journal Year:
2024,
Volume and Issue:
224(2)
Published: Dec. 24, 2024
Synaptic
dysfunction
is
one
of
the
earliest
cellular
defects
observed
in
Alzheimer's
disease
(AD)
and
Parkinson's
(PD),
occurring
before
widespread
protein
aggregation,
neuronal
loss,
cognitive
decline.
While
field
has
focused
on
aggregation
Tau
α-Synuclein
(α-Syn),
emerging
evidence
suggests
that
these
proteins
may
drive
presynaptic
pathology
even
their
aggregation.
Therefore,
understanding
mechanisms
by
which
α-Syn
affect
terminals
offers
an
opportunity
for
developing
innovative
therapeutics
aimed
at
preserving
synapses
potentially
halting
neurodegeneration.
This
review
focuses
molecular
converge
caused
α-Syn.
Both
have
physiological
roles
synapses.
However,
during
disease,
they
acquire
abnormal
functions
due
to
aberrant
interactions
mislocalization.
We
provide
overview
current
research
different
essential
pathways
influenced
Finally,
we
highlight
promising
therapeutic
targets
maintaining
synaptic
function
both
tauopathies
synucleinopathies.
Acta Physiologica,
Journal Year:
2024,
Volume and Issue:
240(8)
Published: June 5, 2024
Abstract
Aim
Understanding
the
physiological
role
of
ATP6V1A,
a
component
cytosolic
V
1
domain
proton
pump
vacuolar
ATPase,
in
regulating
neuronal
development
and
function.
Methods
Modeling
loss
function
Atp6v1a
primary
murine
hippocampal
neurons
studying
morphology
by
immunoimaging,
electrophysiological
recordings
electron
microscopy.
Results
depletion
affects
neurite
elongation,
stabilization,
excitatory
synapses
prevents
synaptic
rearrangement
upon
induction
plasticity.
These
phenotypes
are
due
to
an
overall
decreased
expression
subunits,
that
leads
impairment
lysosomal
pH‐regulation
autophagy
progression
with
accumulation
aberrant
lysosomes
at
soma
enlarged
vacuoles
boutons.
Conclusions
data
suggest
ATP6V1A
surveillance
integrity
plasticity
highlight
pathophysiological
significance
alteration
is
associated
neurodevelopmental
neurodegenerative
diseases.
The
further
support
pivotal
involvement
flux
maintaining
proper
connectivity
adaptive
properties.
