Circadian Rhythms are Disrupted in Patients and Preclinical Models of Machado-Joseph Disease
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 4, 2025
Abstract
Machado-Joseph
disease
(MJD)
is
caused
by
an
abnormal
CAG
repeat
expansion
in
the
ATXN3
gene,
leading
to
expression
of
a
mutant
ataxin-3
(mutATXN3)
protein.
MJD
patients
exhibit
wide
range
clinical
symptoms,
including
motor
incoordination.
Emerging
evidence
highlights
circadian
rhythm
disruptions
as
early
indicators
and
potential
risk
factors
for
progression
neurodegenerative
conditions.
Circadian
rhythms
are
regulated
internal
clocks,
with
suprachiasmatic
nucleus
(SCN)
acting
master
pacemaker
synchronize
timing
across
body’s
behavioural
physiological
functions.
While
sleep
disturbances
have
been
observed
MJD,
role
clock
regulation
its
pathophysiology
remains
largely
unexplored
spinocerebellar
ataxias.
This
study
aimed
investigate
rhythms,
characterize
associated
disruptions,
uncover
mechanisms
underlying
dysregulation
preclinical
models
MJD.
activity
was
assessed
over
two
weeks
using
actigraphy,
while
YAC-MJD
transgenic
mouse
model,
were
examined
through:
(a)
wheel-running
experiments;
(b)
telemetry-based
monitoring
core
body
temperature;
(c)
immunohistochemical
analysis
neuropeptides
arginine
vasopressin
(AVP)
vasoactive
intestinal
polypeptide
(VIP)
SCN
paraventricular
(PVN);
(d)
RT-qPCR
evaluation
gene
cerebellum.
The
impact
mutATXN3
on
further
investigated
Bmal1
/
Per2-
luciferase
reporters.
exhibited
progressive
decline
robustness
demonstrated
negative
correlations
between
function
index,
rest-activity
fragmentation,
efficiency
scales.
mice
reduced
levels,
increased
required
three
additional
days
re-entrain
after
jet
lag
protocol,
compared
controls.
Disrupted
temperature
observed,
phase
advance
elevated
(∼1
°C)
at
onset
active
period.
Furthermore,
showed
levels
VIP
AVP
PVN,
decreased
Lastly,
we
found
new
mechanistic
that
WT
activates
promoters
Per2
,
whereas
loses
capacity
drive
upon
polyglutamine
expansion.
Overall,
our
findings
indicate
central
dysfunction
impaired
rhythms.
provides
first
robust
paving
way
identification
biomarkers
development
novel
circadian-based
interventions
tackle
possibly
other
Graphical
abstract
Язык: Английский
Epidemiology of Autosomal Dominant Spinocerebellar Ataxias in Latin America: A Systematic review and Meta-analysis
Research Square (Research Square),
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 5, 2025
Abstract
The
Spinocerebellar
Ataxias
(SCAs)
are
a
group
of
autosomal
dominant
neurodegenerative
disorders
characterized
by
progressive
cerebellar
ataxia,
affecting
motor
coordination.
SCAs
reported
globally
with
large
geographical
and
ethnic
differences.
This
systematic
review
meta-analysis
aimed
to
update
the
frequency,
geographic
distribution
in
Latin
America,
including
recently
identified
like
SCA27b.
We
conducted
search
PubMed,
Scopus,
LILACS,
SciELO
Web
Science
databases,
studies
published
from
inception
January
2025.
included
25
for
17
that
met
inclusion
criteria,
representing
total
5,546
participants
across
eleven
countries.
Our
revealed
about
61%
(95%
CI
31–84%)
hereditary
ataxias
America
were
confirmed
have
genetic
diagnosis
SCA.
known
SCA
following
proportions:
MJD/SCA3
(34%),
SCA2
(30%),
SCA10
(9%),
SCA7
(9%)
SCA1
(4%).
Geographic
distributions
notable,
Brazil,
Cuba,
Argentina
Mexico,
predominating
Peru,
Venezuela.
Recently
subtypes,
SCA27B
one
case
SCA4,
Brazil.
In
22
countries
there
no
on
epidemiology
SCAs.
reflects
influence
historical
migrations,
founder
effects,
ancestries,
emphasizing
regional
heterogeneity.
findings
underscore
critical
need
further
epidemiological
studies,
particularly
understudied
region.
Язык: Английский
Palliative Care Approaches in Machado–Joseph Disease
Journal of Palliative Medicine,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 27, 2025
Background:
Spinocerebellar
ataxias
(SCA)
are
a
rare
group
of
neurodegenerative
disorders.
Machado–Joseph
disease
(MJD)
is
the
most
prevalent
autosomal
dominant
ataxia.
No
disease-modifying
treatment
exists;
thus,
palliative
approach
recommended
upon
diagnosis.
Язык: Английский
Epidemiology of Autosomal Dominant Spinocerebellar Ataxias in Latin America: A Systematic Review and Meta-Analysis
The Cerebellum,
Год журнала:
2025,
Номер
24(3)
Опубликована: Март 26, 2025
Язык: Английский
From stigma to increased social acceptance? Living with Machado-Joseph disease in São Miguel, Azores, Portugal
Journal of Community Genetics,
Год журнала:
2024,
Номер
unknown
Опубликована: Авг. 31, 2024
Abstract
This
study
describes
the
experiences
with
stigma
attached
to
Machado-Joseph
disease
(MJD)
in
São
Miguel
Island,
Azores
(Portugal).
We
draw
on
semi-structured
interviews
persons
MJD,
family
members,
healthcare
professionals,
and
direct
care
providers
recruited
through
local
patient’s
association
(
n
=
28).
Qualitative
thematic
analysis
revealed
three
main
themes:
(i)
intense
associated
MJD
past;
(ii)
current
tendency
towards
increased
openness;
(iii)
availability
of
information
about
support.
The
findings
suggest
that
stigmatization
was
more
frequent
past.
Still,
there
is
currently
a
decrease
intensity
perceived
stigma,
accompanied
by
an
increasing
awareness
within
community.
noted
for
playing
pivotal
role
raising
community
fostering
confidence
individuals
their
families
engage
socially,
which
may
help
reduce
or
mitigate
feelings
stigma.
raises
questions
whether
diminished
results
from
heightened
condition,
social
acceptability
gradual
internalization
normalization
among
as
coping
mechanism.
Язык: Английский
Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3/Machado-Joseph disease
Human Genetics,
Год журнала:
2024,
Номер
143(11), С. 1363 - 1378
Опубликована: Окт. 8, 2024
Abstract
Spinocerebellar
ataxia
type
3/Machado-Joseph
disease
(SCA3/MJD)
is
caused
by
the
expansion
of
a
genetically
unstable
polyglutamine-encoding
CAG
repeat
in
ATXN3
.
Longer
alleles
are
generally
associated
with
earlier
onset
and
frequent
intergenerational
expansions
mediate
anticipation
observed
this
disorder.
Somatic
has
also
been
implicated
slowing
rate
somatic
proposed
as
therapeutic
strategy.
Here,
we
utilised
high-throughput
ultra-deep
MiSeq
amplicon
sequencing
to
precisely
define
number
sequence
repeat,
genotype
an
adjacent
single
nucleotide
variant
quantify
blood
buccal
swab
DNA
cohort
individuals
SCA3
from
Azores
islands
(Portugal).
We
revealed
systematic
mis-sizing
high
levels
inaccuracy
traditional
fragment
length
analysis
that
have
important
implications
for
attempts
identify
modifiers
clinical
molecular
phenotypes.
Quantification
multivariate
regression
expected
effects
age
at
sampling
length,
although
effect
was
surprisingly
modest
much
stronger
associations
age.
association
downstream
rs12895357
expansion,
higher
level
compared
blood.
These
data
suggest
locus
patients
or
might
serve
good
biomarker
trials
testing
suppressors
peripheral
exposure.
Язык: Английский
Age-dependent somatic expansion of theATXN3CAG repeat in the blood and buccal cell DNA of individuals with spinocerebellar ataxia type 3
medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Март 15, 2024
Abstract
Spinocerebellar
ataxia
type
3
(SCA3),
a
currently
untreatable
disorder,
is
caused
by
the
expansion
of
genetically
unstable
polyglutamine-encoding
complex
CAG
repeat
in
ATXN3
gene.
Longer
alleles
are
generally
associated
with
earlier
onset
and
frequent
intergenerational
expansions
mediate
anticipation
observed
this
disorder.
Somatic
has
also
been
implicated
disease
progression
slowing
rate
somatic
patients
recently
proposed
as
therapeutic
strategy.
Here,
we
utilised
high-throughput
ultra-deep
MiSeq
amplicon
sequencing
to
precisely
define
number
repeats,
exact
sequence
structure,
phased
genotype
an
adjacent
single
nucleotide
polymorphism
accurately
quantify
blood
buccal
cell
DNA
samples
cohort
individuals
SCA3
from
Azores
islands
(Portugal).
We
revealed
systematic
mis-sizing
high
levels
inaccuracy
traditional
fragment
length
analysis
approach
that
have
important
implications
for
attempts
identify
modifiers
clinical
molecular
phenotypes,
including
genetic
instability.
Quantification
expected
effects
age
length,
although
effect
was
surprisingly
modest
much
stronger
associations
at
sampling.
association
downstream
rs12895357
expansion,
higher
level
compared
blood.
Although
lower
per
unit,
average
locus
than
typically
HTT
Huntington
patients.
These
data
suggest
or
might
serve
good
biomarker
trials
testing
suppressors
peripheral
exposure.
Язык: Английский
From stigma to increased social acceptance? Living with Machado-Joseph disease in São Miguel, Azores, Portugal
Research Square (Research Square),
Год журнала:
2024,
Номер
unknown
Опубликована: Май 23, 2024
Abstract
This
study
describes
the
experiences
with
stigma
attached
to
Machado-Joseph
disease
(MJD)
in
São
Miguel
Island,
Azores
(Portugal).
We
draw
on
semi-structured
interviews
persons
MJD,
family
members,
healthcare
professionals
and
direct
care
providers,
recruited
through
local
patient’s
association
(n
=
28).
Qualitative
thematic
analysis
revealed
three
main
themes:
i)
intense
past;
ii)
current
tendency
towards
increased
openness;
availability
of
information
about
MJD
support.
The
findings
suggest
that
stigmatization
was
more
frequent
past,
but
there
is
currently
a
decrease
intensity
perceived
accompanied
by
an
increasing
awareness
within
community.
described
as
playing
key
role
raising
community,
well
fostering
confidence
among
people
their
families
engage
socially,
which
may
help
or
mitigate
feelings
stigma.
raises
questions
into
whether
diminished
stems
from
heightened
condition,
socially
acceptability
stigma,
gradual
internalization
normalization
individuals
coping
mechanism.
Язык: Английский
Global DNA methylation is not elevated in blood samples from Machado-Joseph disease mutation carriers
Epigenetics,
Год журнала:
2024,
Номер
19(1)
Опубликована: Июнь 20, 2024
Machado-Joseph
disease
(MJD)
is
an
autosomal
dominant
spinocerebellar
ataxia
(SCA)
caused
by
a
polyglutamine
expansion
in
the
ataxin-3
protein,
which
initiates
cascade
of
pathogenic
events,
including
transcriptional
dysregulation.
Genotype-phenotype
correlations
MJD
are
incomplete,
suggesting
influence
additional
factors,
such
as
epigenetic
modifications,
underlying
pathogenesis.
DNA
methylation
known
to
impact
pathophysiology
neurodegenerative
disorders
through
gene
expression
regulation
and
increased
has
been
reported
for
other
SCAs.
In
this
work
we
aimed
analyse
global
carriers.
Global
5-mC
levels
were
quantified
blood
samples
33
mutation
carriers
(patients
preclinical
subjects)
healthy
controls,
matched
age,
sex,
smoking
status.
For
subset
16
subjects,
pilot
follow-up
analysis
with
two
time
points
was
also
conducted.
No
differences
found
median
between
controls
no
clinical
or
genetic
variables
detected.
Also,
alterations
observed
over
time.
Our
findings
do
not
support
increase
associated
MJD.
Язык: Английский
Specific Biomarkers in Spinocerebellar Ataxia Type 3: A Systematic Review of Their Potential Uses in Disease Staging and Treatment Assessment
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(15), С. 8074 - 8074
Опубликована: Июль 24, 2024
Spinocerebellar
ataxia
type
3
(SCA3)
is
the
most
common
of
disease
related
to
poly-glutamine
(polyQ)
repeats.
Its
hallmark
pathology
abnormal
accumulation
ataxin
with
a
longer
polyQ
tract
(polyQ-ATXN3).
However,
there
are
other
mechanisms
SCA3
progression
that
require
identifying
trait
and
state
biomarkers
for
more
accurate
diagnosis
prognosis.
Moreover,
identification
potential
pharmacodynamic
targets
assessment
therapeutic
efficacy
necessitates
valid
biomarker
profiles.
The
aim
this
review
was
identify
their
value
in
clinical
trials.
Our
results
show
that,
SCA3,
different
fluid
involved
neurodegeneration,
oxidative
stress,
metabolism,
miRNA
novel
genes.
neurofilament
light
chain
NfL
polyQ-ATXN3
stand
out
as
prevalent
body
fluids
stages.
A
heterogeneity
analysis
revealed
it
may
be
valuable
biomarker,
particularly
when
measured
plasma.
Nonetheless,
since
could
beneficial
approach
tracking
trial
efficacy,
convenient
perform
profile
evaluation
than
rely
on
only
one.
Язык: Английский