bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Oct. 31, 2024
Abstract
Atypical
wild-type
superoxide
dismutase
1
(SOD1)
protein
misfolding
and
deposition
occurs
specifically
within
the
degenerating
substantia
nigra
pars
compacta
(SNc)
in
Parkinson
disease.
Mechanisms
driving
formation
of
this
pathology
relationship
with
SNc
dopamine
neuron
health,
are
yet
to
be
fully
understood.
We
applied
proteomic
mass
spectrometry
synchrotron-based
biometal
quantification
post-mortem
brain
tissues
from
disease
patients
age-matched
controls
uncover
key
factors
underlying
SOD1
disorder.
then
engineered
copper
deficiency
upregulated
levels
a
novel
mouse
strain,
termed
SOCK
mouse,
verify
their
involvement
development
Parkinson-like
impact
on
health.
Soluble
exhibited
altered
post-translational
modifications,
which
may
underlie
changes
enzymatic
activity
aggregation
region.
These
include
decreased
binding,
dysregulation
physiological
glycosylation,
atypical
oxidation
glycation
amino
acid
residues.
demonstrated
that
biochemical
profile
introduced
mice
promotes
same
modifications
midbrain
cortex.
This
accumulates
progressively
age
is
accompanied
by
nigrostriatal
degeneration
dysfunction,
occur
absence
α-synuclein
deposition.
do
not
exhibit
weight
loss
nor
spinal
cord
motor
degeneration,
distinguishing
them
transgenic
mutant
models.
study
provides
first
vivo
evidence
mismetallation
precipitates
misfolding,
dysfunction
brain,
contribute
degeneration.
Our
data
position
as
drug
target
for
disorder,
particular
focus
therapies
capable
correcting
alterations
modifications.
Journal of Neurology,
Journal Year:
2024,
Volume and Issue:
271(6), P. 2992 - 3018
Published: March 30, 2024
Abstract
Tauopathies
are
a
heterogeneous
group
of
neurologic
diseases
characterized
by
pathological
axodendritic
distribution,
ectopic
expression,
and/or
phosphorylation
and
aggregation
the
microtubule-associated
protein
TAU,
encoded
gene
MAPT
.
Neuronal
dysfunction,
dementia,
neurodegeneration
common
features
these
often
detrimental
diseases.
A
neurodegenerative
disease
is
considered
primary
tauopathy
when
mutations/haplotypes
its
cause
TAU
main
feature.
In
case
pathology
observed
but
superimposed
another
hallmark,
condition
classified
as
secondary
tauopathy.
some
tauopathies
(e.g.
-associated
frontotemporal
dementia
(FTD),
progressive
supranuclear
palsy
(PSP),
corticobasal
degeneration
(CBD),
Alzheimer's
(AD))
recognized
significant
pathogenic
driver
disease.
many
tauopathies,
including
Parkinson's
(PD)
Huntington's
(HD),
suggested
to
contribute
development
in
others
Niemann-Pick
(NPC))
may
only
be
bystander.
The
genetic
mechanisms
underlying
not
fully
understood.
this
review,
predispositions
variants
associated
with
both
examined
detail,
assessing
evidence
for
role
conditions.
We
highlight
less
forms
increase
awareness
disorders
involvement
their
pathology.
This
approach
contributes
deeper
understanding
conditions
also
lay
groundwork
potential
TAU-based
therapeutic
interventions
various
tauopathies.
International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(3), P. 1672 - 1672
Published: Jan. 30, 2024
The
water-selective
channel
aquaporin-4
(AQP4)
is
implicated
in
water
homeostasis
and
the
functioning
of
glymphatic
system,
which
eliminates
various
metabolites
from
brain
tissue,
including
amyloidogenic
proteins.
Misfolding
α-synuclein
protein
its
post-translational
modifications
play
a
crucial
role
development
Parkinson’s
disease
(PD)
other
synucleopathies,
leading
to
formation
cytotoxic
oligomers
aggregates
that
cause
neurodegeneration.
Human
animal
studies
have
shown
an
interconnection
between
AQP4
dysfunction
accumulation;
however,
specific
these
mechanisms
remains
unclear.
This
review
summarizes
current
knowledge
on
progression
pathology,
considering
possible
effects
dysregulation
molecular
can
impact
modification,
accumulation
aggregation.
It
also
highlights
future
directions
help
study
protective
during
PD
neurodegenerative
diseases.
Neurology,
Journal Year:
2025,
Volume and Issue:
104(3)
Published: Jan. 13, 2025
Lewy
body
diseases
(LBDs)
such
as
Parkinson
disease
(PD)
feature
increased
deposition
of
α-synuclein
(α-syn)
in
cutaneous
sympathetic
noradrenergic
nerves.
The
pathophysiologic
significance
intraneuronal
α-syn
is
unclear.
We
reviewed
data
about
immunoreactive
α-syn,
tyrosine
hydroxylase
(TH,
a
marker
catecholaminergic
fibers),
and
the
neurotransmitter
norepinephrine
(NE)
skin
biopsies
from
control
participants
patients
with
PD,
related
LBD
pure
autonomic
failure
(PAF),
non-LBD
synucleinopathy
multiple
system
atrophy
(MSA),
or
neurologic
postacute
sequelae
severe
acute
respiratory
syndrome
coronavirus
2
(neuro-PASC).
In
retrospective
observational
study,
we
α-syn-TH
colocalization
indexes
TH
signal
intensities
arrector
pili
muscles,
blood
vessels,
sweat
glands
neck
NE
concentrations
simultaneously
obtained
thigh
studied
at
NIH
Clinical
Center.
LBD,
MSA,
group
were
assessed
by
analyses
variance
Tukey
post
hoc
test
for
comparisons.
Similar
performed
PD
neuro-PASC
vs
control.
Dermal
examined
18
controls
(mean
age
58
years,
50%
female)
53
(66,
34%),
15
MSA
(61,
33%),
11
(52,
82%)
patients.
had
higher
than
difference
=
1.495,
95%
CI
1.081-1.909,
p
<
0.0001)
all
3
constituents
(arrector
pili:
mean
2.743,
1.608-3.879,
0.0001;
vessels:
2.157,
1.095-3.219,
glands:
4.136,
1.704-6.567,
0.0001).
groups
did
not
differ
either
NE.
elevated
compared
controls,
also
no
differences
contents.
LBDs
entail
biopsies,
without
evidence
local
denervation
deficiency.
results
fail
to
support
toxicity
nerves
neuro-PASC.
raise
possibility
part
postinfectious
immune
inflammatory
processes.
Science Advances,
Journal Year:
2024,
Volume and Issue:
10(6)
Published: Feb. 9, 2024
Alpha-synuclein
(αSyn)
protein
levels
correlate
with
the
risk
and
severity
of
Parkinson’s
disease
related
neurodegenerative
diseases.
Lowering
αSyn
is
being
actively
investigated
as
a
therapeutic
modality.
Here,
we
systematically
map
regulatory
network
that
controls
endogenous
using
sequential
CRISPR-knockout
-interference
screens
in
an
gene
(
SNCA
)–tagged
cell
line
induced
pluripotent
stem
cell–derived
neurons
(iNeurons).
We
uncover
modifiers
at
multiple
layers,
amino-terminal
acetyltransferase
B
(NatB)
enzymes
most
potent
both
lines.
Amino-terminal
acetylation
protects
cytosolic
from
rapid
degradation
by
proteasome
Ube2w-dependent
manner.
Moreover,
show
pharmacological
inhibition
methionyl-aminopeptidase
2,
regulator
NatB
complex
formation,
attenuates
iNeurons
carrying
triplication.
Together,
our
study
reveals
several
networks
control
αSyn,
identifies
mechanisms
mediating
nonacetylated
illustrates
potential
pathways
for
decreasing
synucleinopathies.
International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(20), P. 11198 - 11198
Published: Oct. 18, 2024
Parkinson’s
disease
(PD)
is
a
progressive
age-related
neurodegenerative
disorder
affecting
millions
of
people
worldwide.
Essentially,
it
characterised
by
selective
degeneration
dopamine
neurons
the
nigro-striatal
pathway
and
intraneuronal
aggregation
misfolded
α-synuclein
with
formation
Lewy
bodies
neurites.
Moreover,
specific
small
molecules
intermediary
metabolism
may
have
definite
pathophysiological
role
in
PD.
These
include
dopamine,
levodopa,
reduced
glutathione,
glutathione
disulfide/oxidised
micronutrients
thiamine
ß-Hydroxybutyrate.
Recent
research
indicates
that
these
can
interact
regulate
its
folding
potential
aggregation.
In
this
review,
we
discuss
current
knowledge
on
interactions
between
both
brain
relevant
to
PD,
many
other
natural
synthetic
Additionally,
analyse
some
molecular
mechanisms
potentially
involved.
A
better
understanding
relevance
for
development
rational
future
therapies.
particular,
our
observations
suggest
ß-Hydroxybutyrate
might
synergistic
therapeutic
halting
or
reversing
progression
PD
neuronal
disorders.
Journal of Autoimmunity,
Journal Year:
2025,
Volume and Issue:
152, P. 103390 - 103390
Published: March 1, 2025
Aggregates
of
α-synuclein
(α-Syn)
are
the
major
component
Lewy
bodies
associated
with
Parkinson's
disease.
Recently,
naturally
occurring
autoantibodies
against
(α-Syn-nAbs)
were
detected.
Herein
we
have
isolated
and
further
characterized
such
α-Syn-nAbs.
Using
an
affinity
column
coated
α-Syn,
α-Syn-nAbs
from
a
commercially
available
intravenous
Immunoglobulin
(IVIg)
preparation.
A
methodological
approach
based
on
ELISA,
Western
blotting
immunoprecipitation
as
well
surface
plasmon
resonance,
was
used
to
determine
binding
capacity
α-Syn.
The
epitope
determined
via
peptide
array
membrane
functionality
tested
in
vitro
using
toxicity
fibrillation
assay.
display
strong
α-Syn
demonstrated
by
analysis.
affinities
purified
analyzed
detail
resonance
(Biacore).
that
is
recognized
nAbs
fully
determined.
sequence
within
non-amyloid
(NAC)-Region
crucial
for
Furthermore,
had
inhibitory
effect
fibril
formation
also
able
specifically
reverse
oligomers
species
human
neuroblastoma
(SH-SY5Y)
cells.
Our
results
emphasize
possible
importance
pathogenesis
Since
detectable
serum
cerebrospinal
fluid
interfere
pathological
events
they
may
provide
candidate
treatment
Acta Neuropathologica,
Journal Year:
2025,
Volume and Issue:
149(1)
Published: March 5, 2025
Abstract
Atypical
wild-type
superoxide
dismutase
1
(SOD1)
protein
misfolding
and
deposition
occurs
specifically
within
the
degenerating
substantia
nigra
pars
compacta
(SNc)
in
Parkinson
disease.
Mechanisms
driving
formation
of
this
pathology
relationship
with
SNc
dopamine
neuron
health
are
yet
to
be
fully
understood.
We
applied
proteomic
mass
spectrometry
synchrotron-based
biometal
quantification
post-mortem
brain
tissues
from
disease
patients
age-matched
controls
uncover
key
factors
underlying
SOD1
disorder.
also
engineered
two
these
-
copper
deficiency
upregulated
levels
into
a
novel
mouse
strain,
termed
SOCK
mouse,
verify
their
involvement
development
Parkinson-like
impact
on
health.
Soluble
exhibited
altered
post-translational
modifications,
which
may
underlie
changes
enzymatic
activity
aggregation
region.
These
include
decreased
binding,
dysregulation
physiological
glycosylation,
atypical
oxidation
glycation
amino
acid
residues.
demonstrated
that
biochemical
profile
introduced
mice
promotes
same
modifications
midbrain
cortex.
This
accumulates
progressively
age
is
accompanied
by
nigrostriatal
degeneration
dysfunction,
occur
absence
α-synuclein
deposition.
do
not
exhibit
weight
loss
nor
spinal
cord
motor
degeneration,
distinguishing
them
transgenic
mutant
models.
study
provides
first
vivo
evidence
mismetallation
precipitates
misfolding,
brain,
contribute
degeneration.
Our
data
position
as
drug
target
for
disorder,
particular
focus
therapies
capable
correcting
alterations
modifications.
