Journal of Neurology Neurosurgery & Psychiatry,
Journal Year:
2020,
Volume and Issue:
91(7), P. 740 - 749
Published: May 13, 2020
The
rapid
eye
movement
sleep
behavioural
disorder
(RBD)
population
is
an
ideal
study
for
testing
disease-modifying
treatments
synucleinopathies,
since
RBD
represents
early
prodromal
stage
of
synucleinopathy
when
neuropathology
may
be
more
responsive
to
treatment.
While
clonazepam
and
melatonin
are
most
commonly
used
as
symptomatic
RBD,
clinical
trials
also
needed
identify
evidence-based
treatments.
A
comprehensive
framework
both
treatment
in
described,
including
potential
the
pipeline,
cost-effective
participant
recruitment
selection,
design,
outcomes
dissemination
results.
For
trials,
recommended
primary
outcome
phenoconversion
overt
synucleinopathy,
stratification
features
should
select
a
at
high
risk
phenoconversion,
enable
trials.
objective
polysomnogram-based
measurement
RBD-related
movements
vocalisations
measure,
rather
than
subjective
scales
or
diaries.
Mobile
technology
episodes
ambulatory
setting,
advances
imaging,
biofluid,
tissue,
neurophysiological
biomarkers
will
efficient
but
still
development.
Increasing
awareness
among
general
public
medical
community
coupled
with
timely
diagnosis
these
diseases
facilitate
progress
development
therapeutics
associated
neurodegenerative
disorders.
npj Parkinson s Disease,
Journal Year:
2021,
Volume and Issue:
7(1)
Published: July 26, 2021
With
the
advent
of
genetic
era
in
Parkinson's
disease
(PD)
research
1997,
α-synuclein
was
identified
as
an
important
player
a
complex
neurodegenerative
that
affects
>10
million
people
worldwide.
PD
has
been
estimated
to
have
economic
impact
$51.9
billion
US
alone.
Since
initial
association
with
PD,
hundreds
researchers
contributed
elucidating
functions
normal
and
pathological
states,
these
remain
critical
areas
for
continued
research.
this
position
paper
authors
strive
achieve
two
goals:
first,
succinctly
summarize
features
define
α-synuclein's
varied
roles,
they
are
known
today;
second,
identify
most
pressing
knowledge
gaps
delineate
multipronged
strategy
future
goal
enabling
therapies
stop
or
slow
progression
PD.
Pharmacological Reviews,
Journal Year:
2022,
Volume and Issue:
74(1), P. 207 - 237
Published: Jan. 1, 2022
Parkinson9s
disease
(PD)
is
the
second
most
common
neurodegenerative
disorder
and
fastest
growing
neurologic
in
world,
yet
no
disease-modifying
therapy
available
for
this
disabling
condition.
Multiple
lines
of
evidence
implicate
protein
α-synuclein
(α-Syn)
pathogenesis
PD,
as
such,
there
intense
interest
targeting
α-Syn
potential
modification.
also
a
key
pathogenic
other
synucleionpathies,
commonly
dementia
with
Lewy
bodies.
Thus,
therapeutics
will
have
utility
these
disorders
well.
Here
we
discuss
various
approaches
that
are
being
investigated
to
prevent
mitigate
toxicity
including
clearing
its
pathologic
aggregates
from
brain
using
immunization
strategies,
inhibiting
misfolding
aggregation,
reducing
expression
level,
enhancing
cellular
clearance
mechanisms,
preventing
cell-to-cell
transmission
within
perhaps
periphery,
proteins
associated
or
implicated
PD
contribute
toxicity.
We
pipeline
harness
strategies.
Finally,
challenges
opportunities
field
discovery
development
modification
PD.
Significance
Statement
disorder,
which
therapies
remain
major
unmet
need.
A
large
body
points
well
bodies,
making
it
leading
therapeutic
interest.
This
review
discusses
progress
made
date
toward
discovering
developing
would
slow
stop
progression
diseases.
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: March 29, 2024
Abstract
The
defining
feature
of
Parkinson
disease
(PD)
and
Lewy
body
dementia
(LBD)
is
the
accumulation
alpha-synuclein
(Asyn)
fibrils
in
bodies
neurites.
Here
we
develop
validate
a
method
to
amplify
Asyn
extracted
from
LBD
postmortem
tissue
samples
use
solid
state
nuclear
magnetic
resonance
(SSNMR)
studies
determine
atomic
resolution
structure.
Amplified
comprise
mixture
single
protofilament
two
with
very
low
twist.
fold
highly
similar
determined
by
recent
cryo-electron
microscopy
study
for
minority
population
twisted
tissue.
These
results
expand
structural
characterization
approaches
studying
mechanisms,
imaging
agents
therapeutics
targeting
Asyn.
Parkinson's
disease
(PD)
is
a
degenerative
neurological
condition
marked
by
the
gradual
loss
of
dopaminergic
neurons
in
substantia
nigra
pars
compacta.
The
precise
etiology
PD
remains
unclear,
but
emerging
evidence
suggests
significant
role
for
disrupted
autophagy-a
crucial
cellular
process
maintaining
protein
and
organelle
integrity.
Neurobiology of Disease,
Journal Year:
2018,
Volume and Issue:
124, P. 276 - 288
Published: Oct. 28, 2018
Aggregation
of
α-synuclein
(α-syn)
is
neuropathologically
and
genetically
linked
to
Parkinson's
disease
(PD).
Since
stereotypic
cell-to-cell
spreading
α-syn
pathology
believed
contribute
progression,
immunotherapy
with
antibodies
directed
against
considered
a
promising
therapeutic
approach
for
slowing
progression.
Here
we
report
the
identification,
binding
characteristics,
efficacy
in
PD
mouse
models
human-derived
antibody
BIIB054,
which
currently
under
investigation
Phase
2
clinical
trial
PD.
BIIB054
was
generated
by
screening
human
memory
B-cell
libraries
from
healthy
elderly
individuals.
Epitope
mapping
studies
conducted
using
peptide
scanning,
X-ray
crystallography,
mutagenesis
show
that
binds
residues
1-10.
highly
selective
aggregated
forms
at
least
an
800-fold
higher
apparent
affinity
fibrillar
versus
monomeric
recombinant
strong
preference
brain
tissue.
discriminates
between
monomers
oligomeric/fibrillar
based
on
high
avidity
aggregates,
driven
weak
monovalent
fast
kinetics.
In
three
different
intracerebrally
inoculated
preformed
fibrils,
treatment
attenuated
pathology,
rescued
motor
impairments,
reduced
loss
dopamine
transporter
density
dopaminergic
terminals
striatum.
The
preclinical
data
reported
here
provide
compelling
rationale
development
prevention
