Brain,
Год журнала:
2020,
Номер
143(9), С. 2803 - 2817
Опубликована: Июнь 23, 2020
Accumulation
of
phosphorylated
tau
is
a
key
pathological
feature
Alzheimer's
disease.
Phosphorylated
accumulation
causes
synaptic
impairment,
neuronal
dysfunction
and
formation
neurofibrillary
tangles.
The
actions
are
mediated
by
surrounding
proteins;
however,
comprehensive
understanding
the
proteins
that
interacts
with
in
disease
surprisingly
limited.
Therefore,
aim
this
study
was
to
determine
interactome.
To
end,
we
used
two
complementary
proteomics
approaches:
(i)
quantitative
performed
on
tangles
microdissected
from
patients
advanced
disease;
(ii)
affinity
purification-mass
spectrometry
identify
which
these
specifically
bound
tau.
We
identified
542
This
included
abundant
detection
many
known
be
present
such
as
tau,
ubiquitin,
neurofilament
apolipoprotein
E.
Affinity
confirmed
75
interacted
PHF1-immunoreactive
Twenty-nine
have
been
previously
associated
therefore
validating
our
proteomic
approach.
More
importantly,
34
had
total
but
not
yet
linked
directly
(e.g.
protein
VAMP2,
vacuolar-ATPase
subunit
ATP6V0D1);
therefore,
provide
new
evidence
they
interact
In
addition,
also
12
novel
proteins,
physiologically
or
pathologically
RNA
binding
HNRNPA1).
Network
analysis
showed
interactome
enriched
involved
ubiquitination
pathway
phagosome
maturation.
Importantly,
were
able
pinpoint
specific
pathways
for
first
time,
providing
potential
pathogenic
mechanisms
can
explored
future
studies.
Combined,
results
reveal
drug
targets
treatment
tauopathies
insight
into
how
mediates
its
toxicity
Brain,
Год журнала:
2015,
Номер
138(10), С. 2814 - 2833
Опубликована: Авг. 17, 2015
Abnormal
tau
lesions
(non-argyrophilic
pretangle
material,
argyrophilic
neuropil
threads,
neurofibrillary
tangles)
in
select
types
of
neurons
are
crucial
for
the
pathogenesis
sporadic
Alzheimer's
disease.
Ongoing
formation
these
persists
into
end-stage
disease
and
is
not
subject
to
remission.
The
early
phase
a
focus
increasing
interest
because
only
abnormal
forms
microtubule-associated
protein
involved
at
that
point
and,
contrast
late-stage
when
amyloid-β
deposition
present,
this
temporally
closer
prevailing
conditions
induce
pathological
process
underlying
Extracellular
aggregated
may
be
produced
under
by
nerve
cells
contain
tau.
One
potential
trigger
hyperphosphorylation
conformational
change
presence
non-endogenous
pathogen.
Subsequently,
predictable
regional
distribution
pattern
develops
phylogenetically
late-appearing
ontogenetically
late-maturing
connected
via
their
axons.
It
hoped
hypotheses
drawn
from
considerations,
as
well
recent
dissemination
models,
studies
variant
conformers,
imaging
will
encourage
development
new
preventative
disease-modifying
strategies.
Frontiers in Neurology,
Год журнала:
2013,
Номер
4
Опубликована: Янв. 1, 2013
Fibrillar
deposits
of
highly
phosphorylated
tau
are
a
key
pathological
feature
several
neurodegenerative
tauopathies
including
Alzheimer's
disease
(AD)
and
some
frontotemporal
dementias.
Increasing
evidence
suggests
that
the
presence
these
end-stage
neurofibrillary
lesions
do
not
cause
neuronal
loss,
but
rather
alterations
to
soluble
proteins
induce
neurodegeneration.
In
particular,
aberrant
phosphorylation
is
acknowledged
be
process,
influencing
structure,
distribution,
function
in
neurons.
Although
typically
described
as
cytosolic
protein
associates
with
microtubules
regulates
axonal
transport,
additional
functions
have
recently
been
demonstrated,
roles
DNA
stabilization,
synaptic
function.
Most
recently,
studies
examining
trans-synaptic
spread
pathology
models
suggested
potential
role
for
extracellular
cell
signaling
pathways
intrinsic
Here
we
review
showing
plays
tauopathies.
We
also
comment
on
tractability
altering
phosphorylation-dependent
therapeutic
intervention
AD
related
disorders.
Molecular Neurodegeneration,
Год журнала:
2017,
Номер
12(1)
Опубликована: Дек. 1, 2017
Alzheimer's
disease
(AD)
is
behaviorally
identified
by
progressive
memory
impairment
and
pathologically
characterized
the
triad
of
β-amyloid
plaques,
neurofibrillary
tangles,
neurodegeneration.
Genetic
mutations
risk
factors
have
been
that
are
either
causal
or
modify
progression.
These
genetic
pathological
features
serve
as
basis
for
creation
validation
mouse
models
AD.
Efforts
made
in
past
quarter-century
produced
over
100
genetically
engineered
lines
recapitulate
some
aspects
AD
clinicopathology.
valuable
resources
understanding
interactions
contribute
to
cellular
reactions
engaged
response.
Here
we
focus
on
widely
used
stalwarts
field
recently
developed
bellwethers
future.
Rather
than
providing
a
summary
each
model,
endeavor
compare
contrast
approaches
employed
discuss
their
respective
advantages
limitations.
We
offer
critical
account
variables
which
may
inconsistent
findings
should
be
considered
when
choosing
model
interpreting
results.
hope
present
an
insightful
review
current
provide
practical
guide
selecting
best
matched
experimental
question
at
hand.
International Journal of Molecular Sciences,
Год журнала:
2014,
Номер
15(3), С. 4671 - 4713
Опубликована: Март 18, 2014
Tau
protein
is
abundant
in
the
central
nervous
system
and
involved
microtubule
assembly
stabilization.
It
predominantly
associated
with
axonal
microtubules
present
at
lower
level
dendrites
where
it
engaged
signaling
functions.
Post-translational
modifications
of
tau
its
interaction
several
proteins
play
an
important
regulatory
role
physiology
tau.
As
a
consequence
abnormal
expression,
redistributed
from
neuronal
processes
to
soma
forms
toxic
oligomers
or
aggregated
deposits.
The
accumulation
increasingly
recognized
as
neuropathological
hallmark
number
dementia
disorders
known
tauopathies.
Dysfunction
may
contribute
collapse
cytoskeleton,
thereby
causing
improper
anterograde
retrograde
movement
motor
their
cargos
on
microtubules.
These
disturbances
intraneuronal
compromise
synaptic
transmission
well
trophic
support
mechanisms
neurons.
