ABSTRACT
Mammalian
prion
diseases
are
infectious
neurodegenerative
caused
by
the
self-templating
form
of
protein
PrP
Sc
.
Much
evidence
supports
hypothesis
that
prions
exist
as
a
mixture
dominant
strain
and
minor
strains.
While
it
is
known
can
infect
new
species,
relative
contribution
strains
in
crossing
species
barrier
unknown.
We
previously
identified
from
biologically
cloned
drowsy
(DY)
hamster-adapted
transmissible
mink
encephalopathy
(TME).
Here
we
show
these
have
increased
infection
efficiency
to
rabbit
kidney
epithelial
cells
express
hamster
C
compared
DY
TME.
Using
misfolding
cyclic
amplification
(PMCA),
found
TME
failed
convert
mouse
,
even
after
several
serial
passages.
In
contrast,
isolated
robustly
converted
first
round
PMCA.
This
observation
indicates
mutant
spectra
contribute
barrier.
Additionally,
PMCA
conversion
for
tested
was
significantly
different
each
other
short-incubation
period
HY
suggests
diversity
may
be
greater
than
anticipated.
These
observations
further
expand
our
understanding
mechanisms
underlying
effect
has
implications
assessing
zoonotic
potential
prions.
IMPORTANCE
Prions
cattle
with
bovine
spongiform
transmitted
humans,
whereas
scrapie
sheep
goats
likely
not,
suggesting
some
cross
barriers
more
easily
others.
composed
strains,
population
adapt
replicative
environments
Recently,
were
TME,
differed
properties
strain,
also
host
range
novel
findings
provide
interspecies
transmission,
underscoring
significance
components
important
biological
processes.
ACS Chemical Neuroscience,
Год журнала:
2024,
Номер
15(11), С. 2265 - 2282
Опубликована: Май 14, 2024
Prion
diseases
are
invariably
fatal
neurodegenerative
of
humans
and
other
animals
for
which
there
no
effective
treatment
options.
Previous
work
from
our
laboratory
identified
phenethylpiperidines
as
a
novel
class
anti-prion
compounds.
While
working
to
identify
the
molecular
target(s)
these
molecules,
we
unexpectedly
discovered
ten
antiprion
compounds
based
on
their
known
ability
bind
sigma
receptors,
σ1R
σ2R,
currently
being
tested
therapeutic
or
diagnostic
targets
cancer
neuropsychiatric
disorders.
Surprisingly,
however,
knockout
respective
genes
encoding
σ2R
(Sigmar1
Tmem97)
in
prion-infected
N2a
cells
did
not
alter
activity
compounds,
demonstrating
that
receptors
direct
responsible
effects
ligands.
Further
investigation
most
potent
molecules
established
they
efficacious
against
multiple
prion
strains
protect
downstream
prion-mediated
synaptotoxicity.
precise
details
mechanism
action
remain
be
determined,
present
forms
basis
further
preclinical
studies.
Given
utility
several
including
rimcazole
haloperidol
conditions,
(+)-pentazocine
neuropathic
pain,
ongoing
clinical
trials
SA
4503
ANAVEX2-73
ischemic
stroke
Alzheimer's
disease,
respectively,
this
has
immediate
implications
human
disease.
Scientific Reports,
Год журнала:
2024,
Номер
14(1)
Опубликована: Фев. 29, 2024
Abstract
Recently,
electron
cryo-microscopy
(cryo-EM)
maps
of
fibrils
from
the
brains
mice
and
hamsters
with
five
infectious
scrapie
strains
have
been
published
deposited
in
microscopy
data
bank
(EMDB).
As
noted
by
primary
authors,
contain
a
second
component
other
than
protein.
The
aim
present
study
was
to
identify
nature
this
using
an
silico
approach.
Extra
densities
(EDs)
containing
were
continuous,
straight,
axial,
at
right
angles
protein
rungs
within
hydrogen-bonding
distance
protein,
consistent
structural
role.
EDs
co-located
strips
basic
residues,
notably
lysines,
formed
conspicuous
cladding
over
parts
N-terminal
lobe
A
Y-shaped
polymer
RNA
found,
places
forming
single
chain
one
location
duplex,
comprising
two
antiparallel
chains,
raising
intriguing
possibility
replicative
behaviour.
To
reflect
monotonous
interface,
it
is
suggested
that
may
be
short
tandem
repeat.
Fibrils
patients
Alzheimer’s
disease,
Parkinson’s
amyotrophic
lateral
sclerosis
neurodegenerations
also
similar
aetiology.
Journal of Parkinson s Disease,
Год журнала:
2024,
Номер
14(6), С. 1095 - 1103
Опубликована: Июль 19, 2024
Pre-formed
fibrils
(PFFs)
made
from
recombinant
α-synuclein
are
broadly
used
throughout
the
field
in
cellular
and
animal
models
of
Parkinson's
disease.
However,
their
ability
to
successfully
recapitulate
disease
biology
is
a
controversial
topic.
In
this
article,
two
researchers
debate
issue
with
Amanda
Woerman
taking
view
that
PFFs
model
synucleinopathy
but
not
disease,
while
Kelvin
Luk
defends
use
as
an
important
tool
field.
ABSTRACT
Mammalian
prion
diseases
are
infectious
neurodegenerative
caused
by
the
self-templating
form
of
protein
PrP
Sc
.
Much
evidence
supports
hypothesis
that
prions
exist
as
a
mixture
dominant
strain
and
minor
strains.
While
it
is
known
can
infect
new
species,
relative
contribution
strains
in
crossing
species
barrier
unknown.
We
previously
identified
from
biologically
cloned
drowsy
(DY)
hamster-adapted
transmissible
mink
encephalopathy
(TME).
Here
we
show
these
have
increased
infection
efficiency
to
rabbit
kidney
epithelial
cells
express
hamster
C
compared
DY
TME.
Using
misfolding
cyclic
amplification
(PMCA),
found
TME
failed
convert
mouse
,
even
after
several
serial
passages.
In
contrast,
isolated
robustly
converted
first
round
PMCA.
This
observation
indicates
mutant
spectra
contribute
barrier.
Additionally,
PMCA
conversion
for
tested
was
significantly
different
each
other
short-incubation
period
HY
suggests
diversity
may
be
greater
than
anticipated.
These
observations
further
expand
our
understanding
mechanisms
underlying
effect
has
implications
assessing
zoonotic
potential
prions.
IMPORTANCE
Prions
cattle
with
bovine
spongiform
transmitted
humans,
whereas
scrapie
sheep
goats
likely
not,
suggesting
some
cross
barriers
more
easily
others.
composed
strains,
population
adapt
replicative
environments
Recently,
were
TME,
differed
properties
strain,
also
host
range
novel
findings
provide
interspecies
transmission,
underscoring
significance
components
important
biological
processes.
