bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2022,
Номер
unknown
Опубликована: Окт. 24, 2022
The
role
of
genomic
variants
in
disease,
including
cancer,
continues
to
expand
thanks
the
advent
advanced
sequencing
techniques
integrated
into
clinical
practice.
rapid
growth
identification
has
led
classification
many
as
Variants
Uncertain
Significance
(VUS)
or
with
conflicting
evidence,
posing
challenges
their
interpretation
and
application.
Here
we
introduce
MAVISp
(
M
ulti-layered
A
ssessment
V
arIants
by
S
tructure
for
p
roteins),
a
modular
structural
framework
variant
interpretation.
We
also
provide
web
server
https://services.healthtech.dtu.dk/services/MAVISp-1.0/
),
enhance
data
accessibility,
consultation,
re-usability.
Currently,
offers
analyses
more
than
200
different
proteins,
encompassing
approximately
85000
variants.
dedicated
team
biocurators
reviewers
continuously
analyze
update
protein
targets
using
standardized
workflows,
incorporating
high-throughput
free
energy
calculations
biomolecular
simulations.
Here,
illustrate
potential
approach
through
selection
case
studies.
Our
aids
variants,
particularly
those
categorized
VUS,
holds
great
advancing
understanding
application
genomics
disease
research.
International Journal of Molecular Sciences,
Год журнала:
2023,
Номер
24(4), С. 3754 - 3754
Опубликована: Фев. 13, 2023
Alzheimer’s
disease
(AD)
is
the
most
common
neurodegenerative
in
world.
It
classified
as
familial
and
sporadic.
The
dominant
or
autosomal
presentation
represents
1–5%
of
total
number
cases.
categorized
early
onset
(EOAD;
<65
years
age)
presents
genetic
mutations
presenilin
1
(PSEN1),
2
(PSEN2),
Amyloid
precursor
protein
(APP).
Sporadic
AD
95%
cases
late-onset
(LOAD),
occurring
patients
older
than
65
age.
Several
risk
factors
have
been
identified
sporadic
AD;
aging
main
one.
Nonetheless,
multiple
genes
associated
with
different
neuropathological
events
involved
LOAD,
such
pathological
processing
beta
(Aβ)
peptide
Tau
protein,
well
synaptic
mitochondrial
dysfunctions,
neurovascular
alterations,
oxidative
stress,
neuroinflammation,
among
others.
Interestingly,
using
genome-wide
association
study
(GWAS)
technology,
many
polymorphisms
LOAD
identified.
This
review
aims
to
analyze
new
findings
that
are
closely
related
pathophysiology
AD.
Likewise,
it
analyzes
date
through
GWAS
a
high
low
developing
this
neurodegeneration.
Understanding
variability
will
allow
for
identification
biomarkers
opportune
therapeutic
targets
Phenomics,
Год журнала:
2023,
Номер
3(4), С. 333 - 349
Опубликована: Апрель 3, 2023
Abstract
Years
of
intensive
research
has
brought
us
extensive
knowledge
on
the
genetic
and
molecular
factors
involved
in
Alzheimer's
disease
(AD).
In
addition
to
mutations
three
main
causative
genes
familial
AD
(FAD)
including
presenilins
amyloid
precursor
protein
genes,
studies
have
identified
several
as
most
plausible
for
onset
progression
FAD,
such
triggering
receptor
expressed
myeloid
cells
2
,
sortilin-related
1
adenosine
triphosphate-binding
cassette
transporter
subfamily
A
member
7
.
The
apolipoprotein
E
ε4
allele
is
reported
be
strongest
risk
factor
sporadic
(SAD),
it
also
plays
an
important
role
FAD.
Here,
we
reviewed
recent
developments
that
contributed
understanding
phenotypes
FAD
compared
them
with
SAD.
We
further
advancements
gene
therapy
discussed
future
perspectives
based
phenotypes.
International Journal of Molecular Sciences,
Год журнала:
2023,
Номер
24(6), С. 5383 - 5383
Опубликована: Март 11, 2023
Alzheimer’s
disease
(AD)
is
an
incurable,
progressive
neurodegenerative
disorder.
AD
a
complex
and
multifactorial
that
responsible
for
60–80%
of
dementia
cases.
Aging,
genetic
factors,
epigenetic
changes
are
the
main
risk
factors
AD.
Two
aggregation-prone
proteins
play
decisive
role
in
pathogenesis:
β-amyloid
(Aβ)
hyperphosphorylated
tau
(pTau).
Both
them
form
deposits
diffusible
toxic
aggregates
brain.
These
biomarkers
Different
hypotheses
have
tried
to
explain
pathogenesis
served
as
platforms
drug
research.
Experiments
demonstrated
both
Aβ
pTau
might
start
processes
necessary
cognitive
decline.
The
two
pathologies
act
synergy.
Inhibition
formation
has
been
old
target.
Recently,
successful
clearance
by
monoclonal
antibodies
raised
new
hopes
treatments
if
detected
at
early
stages.
More
recently,
novel
targets,
e.g.,
improvements
amyloid
from
brain,
application
small
heat
shock
(Hsps),
modulation
chronic
neuroinflammation
different
receptor
ligands,
microglial
phagocytosis,
increase
myelination
revealed
Biomolecules,
Год журнала:
2024,
Номер
14(4), С. 402 - 402
Опубликована: Март 26, 2024
The
changes
in
the
properties
of
three
biological
events
that
occur
with
cerebral
aging
are
discussed.
These
adverse
already
begin
to
develop
early
mid-life
and
gradually
become
more
pronounced
senescence.
Essentially,
they
reflections
progressive
decline
effectiveness
key
processes,
resulting
deviation
essential
biochemical
trajectories
ineffective
ultimately
harmful
variants
these
programs.
emphasis
this
review
is
major
role
played
by
mitochondria
transition
important
processes
toward
deleterious
as
brain
proceeds.
immune
system:
shift
away
from
an
efficient
response
a
unfocused,
continuing
inflammatory
condition.
Such
state
both
harmful.
Reactive
oxygen
species
intracellular
signaling
systems.
Additionally,
microglial
phagocytic
activity
utilizing
short
lived
reactive
contribute
removal
aberrant
or
dead
cells
bacteria.
transformed
into
excessive,
untargeted,
persistent
generation
pro-oxidant
free
radicals
(oxidative
stress).
normal
neural
transmission
modified
undirected,
chronic
low-level
excitatory
activity.
Each
characterized
occurrence
continuous
inefficient
diffused.
signal/noise
ratio
several
critical
thus
reduced
beneficial
responses
replaced
their
impaired
variants.
Communications Biology,
Год журнала:
2025,
Номер
8(1)
Опубликована: Фев. 7, 2025
Age-related
long-term
disability
is
attracting
increasing
attention
due
to
the
growing
ageing
population
worldwide.
However,
current
understanding
of
senescent
spinal
cord
remains
insufficient.
Bulk
RNA
sequencing
reveals
that
526
genes
are
upregulated
and
300
downregulated
in
cords.
Pathway
enrichment
analysis
differentially
expressed
shows
senescence
cords
related
phagosome
function,
neuroinflammation,
ferroptosis,
necroptosis.
Prediction
upstream
transcription
factors
interactome
identify
Spi1
as
a
factor
potentially
plays
core
role
Spatial
transcriptomics
illustrates
spatial
distribution
transcriptomic
landscape
both
young
identifies
distinct
neuronal
glial
subtypes.
The
ferroptosis-associated
gene
Fth1
aged
Flow
cytometry
increased
accumulation
free
Fe2+
ROS
mixed
cells;
however,
CCK-8
assays
reveal
these
cells
resistant
ferroptosis.
SiRNA
lentivirus
experiments
indicate
overexpression
normal
reduces
their
sensitivity
whereas
knockdown
increases
In
summary,
bulk
elucidate
transcriptional
characteristics
versus
cords,
thus
highlighting
mediating
ferroptosis
resistance
cells.
Multiomics
sheds
light
on
expression
signature
during
process-resistance
via
upregulation
Fth1.
Frontiers in Aging Neuroscience,
Год журнала:
2022,
Номер
14
Опубликована: Июнь 24, 2022
Alzheimer's
disease
(AD)
is
a
complex
neurodegenerative
disorder.
The
relative
contribution
of
the
numerous
underlying
functional
mechanisms
poorly
understood.
To
comprehensively
understand
context
and
distribution
pathways
that
contribute
to
AD,
we
performed
text-mining
generate
an
exhaustive,
systematic
assessment
breadth
diversity
biological
within
corpus
206,324
dementia
publication
abstracts.
A
total
91%
(325/335)
Kyoto
Encyclopedia
Genes
Genomes
(KEGG)
have
publications
containing
association
via
at
least
5
studies,
while
63%
pathway
terms
50
studies
providing
clear
with
AD.
Despite
major
technological
advances,
same
set
top-ranked
been
consistently
related
AD
for
30
years,
including
immune
system,
metabolic
pathways,
cholinergic
synapse,
long-term
depression,
proteasome,
diabetes,
cancer,
chemokine
signaling.
studied
appear
biased:
animal
model
human
subject
prioritize
different
pathways.
Surprisingly,
genetic
discoveries
drug
targeting
are
not
enriched
in
most
frequently
Our
findings
suggest
only
this
disorder
incredibly
complex,
but
its
reach
also
nearly
global.
As
consequence
our
study,
research
results
can
now
be
assessed
wider
literature,
supporting
design
therapies
target
broader
range
mechanisms.
study
explored
www.adpathways.org.
Proceedings of the National Academy of Sciences,
Год журнала:
2023,
Номер
120(36)
Опубликована: Авг. 29, 2023
Across
multiancestry
groups,
we
analyzed
Human
Leukocyte
Antigen
(HLA)
associations
in
over
176,000
individuals
with
Parkinson's
disease
(PD)
and
Alzheimer's
(AD)
versus
controls.
We
demonstrate
that
the
two
diseases
share
same
protective
association
at
HLA
locus.
HLA-specific
fine-mapping
showed
hierarchical
effects
of
