Annals of Neurology,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 16, 2024
Objective
To
identify
biochemical
changes
in
individuals
at
higher
risk
of
developing
amyotrophic
lateral
sclerosis
(ALS)
or
frontotemporal
dementia
(FTD)
via
C9orf72
hexanucleotide
repeat
expansion
(HRE)
heterozygosity.
Methods
Cross‐sectional
observational
study
48
asymptomatic
HRE
carriers,
39
non‐carrier
controls,
19
people
with
sporadic
ALS,
10
14
FTD,
and
FTD.
Relative
abundance
30
pre‐defined
cerebrospinal
fluid
biomarkers
ALS
FTD
were
compared
carriers
age‐matched
controls.
Differential
these
proteins
was
quantified
using
data
independent
acquisition
mass
spectrometry
electro
chemiluminescent
assay
for
neurofilament
light
chain.
Unbiased
analysis
the
entire
proteome
then
carried
out.
Results
Ubiquitin
carboxyl‐hydrolase
isozyme
L1
levels
non‐carriers
(log
2
fold
change
0.20,
FDR‐adjusted
p
‐value
=
0.034),
whereas
chain
did
not
significantly
differ.
remained
elevated
after
matching
groups
by
(
0.011),
adjusting
age,
sex,
levels.
A
significant
difference
also
observed
when
restricting
to
younger
participants
(<37)
matched
level
0.007).
Interpretation
Elevated
ubiquitin
can
occur
absence
increased
levels,
potentially
reflecting
either
compensatory
pathogenic
mechanisms
preceding
rapid
neuronal
loss.
This
brings
forward
window
on
associated
carrier
state,
potential
inform
understanding
penetrance
approaches
prevention.
ANN
NEUROL
2024
Amyotrophic
lateral
sclerosis
(ALS)
and
frontotemporal
dementia
(FTD)
represent
two
extremes
of
a
neurodegenerative
disease
spectrum
characterised
by
overlapping
genetic,
clinical,
neuropathological
features.
This
review
covers
the
intricate
relationship
between
both
ALS
FTD
defects
in
autophagy
endolysosomal
pathway
as
recent
evidence
has
pointed
towards
alterations
these
pathways
being
root
cause
pathogenesis.
Here,
we
current
knowledge
on
interplay
ALS/FTD
lysosomebased
proteostasis
carefully
asses
steps
that
are
impaired
or
FTDcausing
variants.
Finally,
present
comprehensive
overview
therapeutic
strategies
aimed
at
restoring
autophagic
lysosomal
function
potential
avenues
for
mitigating
impact
devastating
diseases.
Through
this
review,
aim
to
enhance
understanding
pathophysiological
mechanisms
involving
and/or
system
underlie
ALS-FTD
underscore
necessity
specific
approaches
target
shared
vulnerabilities.
Aging and Disease,
Год журнала:
2024,
Номер
15(5), С. 2113 - 2113
Опубликована: Янв. 1, 2024
The
diagnosis,
treatment,
and
management
of
dementia
provide
significant
challenges
due
to
its
chronic
cognitive
impairment.
complexity
this
condition
is
further
highlighted
by
the
impact
gene-environment
interactions.
A
recent
strategy
combines
advanced
genomics
precision
medicine
methods
explore
complex
genetic
foundations
dementia.
Utilizing
most
research
in
field
neurogenetics,
importance
precise
data
explaining
variation
seen
patients
can
be
investigated.
Gene-environment
interactions
are
important
because
they
influence
susceptibilities
aid
development
progression
Modified
each
patient's
profile,
has
potential
detect
groups
at
risk
make
previously
unheard-of
predictions
about
course
diseases.
Precision
techniques
have
completely
transform
treatment
diagnosis
methods.
Targeted
medications
that
target
abnormalities
will
probably
appear,
providing
possibility
for
more
efficient
customized
medical
interventions.
Investigating
relationship
between
genes
environment
may
lead
preventive
measures
would
enable
people
change
their
surroundings
minimize
dementia,
leading
improved
lifestyle
affected
people.
This
paper
provides
a
comprehensive
overview
genomic
insights
into
emphasizing
pivotal
role
medicine,
Journal of Education Health and Sport,
Год журнала:
2024,
Номер
59, С. 235 - 246
Опубликована: Фев. 14, 2024
Frontotemporal
dementia
is
a
disease
in
which
atrophic
changes
occur
the
frontal
lobes
and
temporal
of
brain.
dementias
are
clinically,
neuroanatomically
pathologically
diverse
group
diseases
that
collectively
constitute
an
important
cause
young-onset
dementia.
The
most
common
form
frontotemporal
so-called
behavioral
variant
Underlying
these
pathological
degeneration
nerve
cells
(i.e.
neurons),
occurs
through
accumulation
abnormal
proteins
inside
them.
Therefore,
review
current
studies
subject
was
conducted
order
to
access
possible
risk
factors
new
ways
management
treatment
this
complex
disease.
The Journal of Physical Chemistry B,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 23, 2024
Condensation
of
RNA
binding
proteins
(RBPs)
with
is
essential
for
cellular
function.
The
most
common
familial
cause
the
diseases
ALS
and
FTD
C9orf72
repeat
expansion
disorders
that
produce
dipeptide
(DPRs).
We
explore
hypothesis
DPRs
disrupt
native
condensation
behavior
RBPs
through
molecular
interactions
resulting
in
toxicity.
FUS
TDP43
are
two
known
to
be
affected
ALS/FTD.
use
our
previously
developed
1-bead-per-amino
acid
a
newly
3-bead-per-nucleotide
dynamics
model
ternary
phase
diagrams
FUS/TDP43-RNA-DPR
systems.
show
toxic
arginine
containing
(R-DPRs)
can
RBP
condensates
cation-π
strongly
sequester
electrostatic
interactions.
droplet
morphologies
already
modified
at
small
additions
R-DPRs
leading
non-native
FUS/TDP43-encapsulated
marbled
RNA/DPR
core.
Ageing and Neurodegenerative Diseases,
Год журнала:
2024,
Номер
unknown
Опубликована: Фев. 29, 2024
Huntington’s
disease
(HD)
is
an
autosomal
dominant
neurodegenerative
disorder
due
to
a
triplet
repeat
expansion
in
the
HTT
gene.
The
identification
of
this
gene
variation
was
lengthy
process,
but
it
has
since
provided
explanation
clinical
observations
including
variability
age
at
onset
observed
across
generations
(phenomenon
anticipation).
Further
molecular
genetic
investigations
have
allowed
discovery
genes
modifying
phenotype
presenting
differences
terms
and
course
disease.
Pathogenic
variations
also
been
found
other
diseases
with
similar
presentation,
such
as
HD,
allowing
precise
diagnosis.
This
narrative
review
examines
these
data
context
their
historical
development.
Their
implication
our
understanding
disorders
treatment
modalities
highlighted.
