Nature Structural & Molecular Biology,
Год журнала:
2024,
Номер
31(12), С. 1955 - 1963
Опубликована: Дек. 1, 2024
Abstract
Recently,
an
African
ancestry-specific
Parkinson
disease
(PD)
risk
signal
was
identified
at
the
gene
encoding
glucocerebrosidase
(
GBA1
).
This
variant
rs3115534
-G)
is
carried
by
~50%
of
West
PD
cases
and
imparts
a
dose-dependent
increase
in
for
disease.
The
has
varied
frequencies
across
ancestry
groups
but
almost
absent
European
Asian
populations.
high
clinical
therapeutic
interest.
Damaging
biallelic
protein-coding
variants
cause
Gaucher
monoallelic
confer
dementia
with
Lewy
bodies,
likely
reducing
function
glucocerebrosidase.
Interestingly,
noncoding
variant,
suggesting
different
mechanism
action.
Using
full-length
RNA
transcript
sequencing,
we
partial
intron
8
expression
carriers
(G)
not
nonvariant
(T).
Antibodies
targeting
N
terminus
showed
that
this
intron-retained
isoform
protein
coding
subsequent
proteomics
did
identify
shorter
isoform,
based.
Clustered
regularly
interspaced
short
palindromic
repeats
editing
reported
index
)
revealed
sequence
alteration
responsible
driving
production
these
transcripts
containing
8.
Follow-up
analysis
it
key
intronic
branchpoint
and,
therefore,
important
implications
splicing
In
addition,
when
measuring
activity,
reduction
carriers.
Overall,
report
functional
effect
which
acts
interfering
transcripts,
resulting
reduced
levels
activity.
understanding
reveals
potential
target
underserved
underrepresented
population.
Annals of Neurology,
Год журнала:
2024,
Номер
95(5), С. 831 - 842
Опубликована: Апрель 1, 2024
Parkinson's
disease
(PD)
is
a
global
health
challenge,
yet
historically
studies
of
PD
have
taken
place
predominantly
in
European
populations.
Recent
genetics
research
conducted
non-European
populations
has
revealed
novel
population-specific
genetic
loci
linked
to
risk,
highlighting
the
importance
studying
globally.
These
insights
broadened
our
understanding
etiology,
which
crucial
for
developing
disease-modifying
interventions.
This
review
comprehensively
explores
landscape
PD,
emphasizing
scientific
rationale
underrepresented
It
underscores
challenges,
such
as
genotype-phenotype
heterogeneity
and
inclusion
difficulties
participants,
ongoing
need
diverse
inclusive
PD.
ANN
NEUROL
2024;95:831-842.
medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 21, 2025
Abstract
The
genomic
landscape
of
the
Indian
population,
particularly
for
age-related
disorders
like
Parkinson’s
disease
(PD)
remains
underrepresented
in
global
research.
Genetic
variability
PD
has
been
studied
predominantly
European
populations,
offering
limited
insights
into
its
role
within
population.
To
address
this
gap,
we
conducted
first
pan-India
survey
involving
4,806
cases
and
6,364
controls,
complemented
by
a
meta-analysis
integrating
summary
statistics
from
multi-ancestry
(N=611,485).
We
further
leveraged
RNA-sequencing
data
lymphoblastoid
cell
lines
731
individuals
1000
Genomes
project
to
evaluate
expression
key
loci
across
populations.
Our
findings
reveal
higher
genetic
burden
population
compared
Europeans,
accounting
∼30%
previously
unexplained
heritability.
Thirteen
genome-wide
significant
were
identified,
including
two
novel
loci,
with
an
additional
three
uncovered
through
meta-analysis.
Polygenic
risk
score
analysis
showed
moderate
transferability
results
highlight
importance
immune
function,
lipid
metabolism
SNCA
aggregation
pathogenesis,
gene
emphasizing
population-specific
differences.
also
established
South
Asia’s
largest
biobank,
providing
foundation
patient-centric
approaches
research
treatment
India.
European Journal of Neuroscience,
Год журнала:
2025,
Номер
61(5)
Опубликована: Март 1, 2025
ABSTRACT
The
release
of
synaptic
vesicles
(SVs)
at
the
junction
is
a
complex
process
involving
various
specialized
proteins
that
work
in
unison.
Among
these,
Bassoon
has
emerged
as
significant
protein,
particularly
noted
for
its
association
with
neurological
and
aging‐related
diseases.
Due
to
structural
functional
roles,
become
focus
recent
research,
especially
understanding
implications
neurodegenerative
psychiatric
disorders.
In
this
narrative
review,
we
explore
Bassoon's
structure,
function,
role
across
spectrum
Neurotransmission
tightly
regulated
relies
on
structures
within
presynaptic
terminal,
such
active
zone
(AZ),
precisely
control
SV
response
incoming
signals.
AZ
comprises
network
large,
multidomain
proteins,
playing
crucial
arrangement.
facilitates
tethering
reloading
SVs,
ensuring
responsiveness
high‐frequency
signals,
while
also
maintaining
proteostasis
presynapse.
This
involves
orchestrating
localization
essential
neuronal
development
plasticity.
large
size
unique
features
enable
it
interact
regulate
function
multiple
making
integral
functioning.
Variants
gene
have
been
linked
variety
conditions,
including
Progressive
Supranuclear
Palsy,
system
atrophy
(MSA),
epilepsy,
schizophrenia,
bipolar
disorder,
Parkinson's
disease.
review
delves
into
pivotal
preserving
integrity
how
disruptions
functions
may
contribute
these
Ageing and Neurodegenerative Diseases,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 28, 2025
Aim:
Parkinson’s
disease
(PD)
is
the
second
most
common
progressive
neurodegenerative
linked
to
genetic
and
other
factors.
The
NUS1
dehydrodolichyl
diphosphate
synthase
subunit
gene
(NUS1)
variants
were
reported
be
associated
with
PD.
In
this
PD-control
cohort,
we
aimed
explore
potential
role
of
in
Methods:
A
cohort
512
Han
Chinese
sporadic
PD
patients
516
ethnically
age-matched
controls
underwent
clinical
evaluation.
Peripheral
blood
samples
then
collected,
whole-exome
sequencing
was
performed.
PD-related
identified
through
screening
verified
using
Sanger
sequencing,
further
classified,
subsequently
analyzed
by
bioinformatics
analysis
tools.
Statistical
conducted
assess
association
between
Results:
Three
heterozygous
missense
variants,
including
c.127G>T
(p.Ala43Ser,
rs1327892878),
c.487G>C
(p.Asp163His,
rs369403261),
c.537T>A
(p.Asp179Glu,
rs28362519),
identified.
Two
rare
c.487G>C,
exclusively
found
patients,
while
low-frequency
variant
detected
both
controls.
Combined
analysis,
a
potentially
pathogenic
may
exert
risk,
though
no
significant
shown
statistical
(all
P
>
0.05).
Conclusion:
Our
findings
suggested
that
seem
not
cause
monogenic
PD,
like
may,
at
most,
susceptibility
Abstract
Gene
dosage
and
point
mutations
in
SNCA,
the
a-synuclein
gene,
give
rise
to
familial
forms
of
Parkinson’s
disease
dementia
with
Lewy
bodies;
an
insertion
mutation
SNCA
causes
juvenile-onset
synucleinopathy.
We
previously
reported
electron
cryo-microscopy
(cryo-EM)
structures
filaments
from
brains
individuals
disease,
bodies
multiple
system
atrophy,
as
well
brain
individual
Here
we
report
cryo-EM
frontal
cortex
two
cases
Parkinsonism
G51D
those
amygdala
a
case
variant
H50Q
a-synuclein.
The
assembled
consist
identical
protofilaments
fold
island
B,
but
without
identified
disconnected
density
A.
protofilament
interface
is
made
residues
E46,
V48
H50.
Filaments
comprise
single
both
islands
A
B.
Unlike
G51D,
pathogenicity
has
been
questioned.
It
remains
be
seen
if
dimerisation
may
also
underlie
other
missense
Moreover,
have
right-handed
helical
twist,
while
atrophy
synucleinopathy
are
left-handed,
which
significant.
Clinical
diagnosis
of
progressive
supranuclear
palsy
(PSP)
is
difficult
due
to
various
phenotypes.
Neuropathologically,
PSP
defined
by
neuronal
loss
in
the
basal
ganglia
and
brainstem
with
widespread
occurrence
neurofibrillary
tangles
(NFTs)
accumulation
phosphorylated
tau
protein
neurons
glial
cells
brain.
We
previously
identified
point
mutation
p.Pro3866Ala
Bassoon
(
BSN
)
gene
a
Japanese
family
PSP‐like
syndrome.
newly
detected
mutations
two
autopsied
cases
carrying
p.Thr2542Met
p.Glu2759Gly,
respectively.
The
case
showed
neurological
symptoms
including
behavioral
abnormalities,
cognitive
dysfunction,
parkinsonism.
Brain
magnetic
resonance
imaging
(MRI)
atrophy
midbrain
tegmentum
hippocampus.
Pathologically,
moderate
severe
gliosis
was
also
found
substantia
nigra,
there
an
almost
complete
transitional
zone
cornu
ammonis
(CA)
1
region
subiculum.
NFTs
were
observed
globus
pallidus,
subthalamic
nucleus,
CA1.
4R
tau‐dominant
tauopathy
detected.
p.Glu2759Gly
symptoms,
right‐dominant
motor
impairment,
right
limping
gait,
postural
instability,
dysfunction.
MRI
mild
left‐dominant
parietal
lobe
atrophy.
thalamus,
putamen,
tegmentum.
Most
immunopositive
for
four‐repeat
tau,
whereas
only
few
them
harbored
three‐repeat
tau‐positive
results
pathological
study
mutations;
these
new
cases.
clinical
phenotypes
similar
first
symptoms.
Accumulation
dominant.
Further
autopsies
further
elucidation
molecular
biological
mechanism
are
desirable.
Frontiers in Neuroscience,
Год журнала:
2024,
Номер
18
Опубликована: Июль 26, 2024
Tauopathy
is
known
to
be
a
major
pathognomonic
finding
in
important
neurodegenerative
diseases
such
as
progressive
supranuclear
palsy
(PSP)
and
corticobasal
degeneration.
However,
the
mechanism
by
which
tauopathy
triggered
remains
elucidated.
We
previously
identified
point
mutation
c.11596C
>
G,
p.Pro3866Ala
medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Фев. 24, 2024
Abstract
Recently,
a
novel
African
ancestry
specific
Parkinson’s
disease
(PD)
risk
signal
was
identified
at
the
gene
encoding
glucocerebrosidase
(
GBA1
).
This
variant
(rs3115534-G)
is
carried
by
∼50%
of
West
PD
cases
and
imparts
dose-dependent
increase
in
for
disease.
The
has
varied
frequencies
across
groups,
but
almost
absent
European
Asian
populations.
high
clinical
therapeutic
interest.
Damaging
bi-allelic
protein-coding
variants
cause
Gaucher
mono-allelic
confer
Dementia
with
Lewy
Bodies,
likely
reducing
function
glucocerebrosidase.
Interestingly,
non-coding
variant,
suggesting
different
mechanism
action.
Using
full
length
RNA
transcript
sequencing,
we
intron
8
expression
carriers
(G)
not
non-variant
(T).
Antibodies
targeting
N-terminus
showed
that
this
intron-retained
isoform
protein
coding
subsequent
proteomics
did
identify
shorter
isoform,
RNA-based.
CRISPR
editing
reported
index
(rs3115534)
revealed
responsible
sequence
alteration
driving
production
these
containing
transcripts.
Follow-up
analysis
it
key
intronic
branchpoint
therefore
important
implications
splicing
In
addition,
when
measuring
activity
reduction
(G).
Overall,
report
functional
effect
which
acts
interfering
transcripts,
resulting
reduced
levels
activity.
understanding
reveals
target
an
underserved
underrepresented
population.
