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
Cold Spring Harbor Perspectives in Biology,
Год журнала:
2017,
Номер
9(7), С. a028035 - a028035
Опубликована: Янв. 6, 2017
Brittany
N.
Dugger1
and
Dennis
W.
Dickson2
1Institute
for
Neurodegenerative
Diseases,
Department
of
Neurology,
Weill
Institute
Neurosciences,
University
California,
San
Francisco,
California
94143
2Mayo
Clinic,
Jacksonville,
Florida
32224
Correspondence:
brittany.dugger{at}ucsf.edu
Physiological Reviews,
Год журнала:
2018,
Номер
98(2), С. 813 - 880
Опубликована: Фев. 28, 2018
Neuronal
cell
death
occurs
extensively
during
development
and
pathology,
where
it
is
especially
important
because
of
the
limited
capacity
adult
neurons
to
proliferate
or
be
replaced.
The
concept
used
simple
as
there
were
just
two
three
types,
so
we
had
work
out
which
type
was
involved
in
our
particular
pathology
then
block
it.
However,
now
know
that
are
at
least
a
dozen
ways
for
die,
blocking
mechanism
may
not
prevent
from
dying,
non-neuronal
cells
also
contribute
neuronal
death.
We
review
here
mechanisms
by
intrinsic
extrinsic
apoptosis,
oncosis,
necroptosis,
parthanatos,
ferroptosis,
sarmoptosis,
autophagic
death,
autosis,
autolysis,
paraptosis,
pyroptosis,
phagoptosis,
mitochondrial
permeability
transition.
next
explore
development,
those
induced
axotomy,
aberrant
cell-cycle
reentry,
glutamate
(excitoxicity
oxytosis),
loss
connected
neurons,
aggregated
proteins
unfolded
protein
response,
oxidants,
inflammation,
microglia.
reassess
forms
occur
stroke
Alzheimer’s
disease,
most
pathologies
involving
discuss
why
has
been
difficult
pinpoint
involved,
if
matters,
molecular
overlap
interplay
between
subroutines,
therapeutic
implications
these
multiple
overlapping
Acta Neuropathologica,
Год журнала:
2017,
Номер
133(5), С. 665 - 704
Опубликована: Апрель 6, 2017
Tau
is
well
established
as
a
microtubule-associated
protein
in
neurons.
However,
under
pathological
conditions,
aberrant
assembly
of
tau
into
insoluble
aggregates
accompanied
by
synaptic
dysfunction
and
neural
cell
death
range
neurodegenerative
disorders,
collectively
referred
to
tauopathies.
Recent
advances
our
understanding
the
multiple
functions
different
locations
inside
outside
neurons
have
revealed
novel
insights
its
importance
diverse
molecular
pathways
including
signalling,
plasticity,
regulation
genomic
stability.
The
present
review
describes
physiological
pathophysiological
properties
how
these
relate
distribution
We
highlight
post-translational
modifications
tau,
which
are
pivotal
defining
modulating
localisation
roles
health
disease.
include
discussion
other
pathologically
relevant
changes
mutation
aggregation,
aspects
impinge
on
propensity
propagate,
potentially
drive
neuronal
loss,
diseased
brain.
Finally,
we
describe
cascade
events
that
may
be
driven
dysfunction,
impaired
axonal
transport,
alterations
synapse
mitochondrial
function,
activation
unfolded
response
defective
degradation.
It
important
fully
understand
attributed
since
this
will
provide
vital
information
involvement
development
pathogenesis
Such
knowledge
enable
determination
critical
should
targeted
potential
therapeutic
agents
developed
for
treatment
Molecular Neurodegeneration,
Год журнала:
2017,
Номер
12(1)
Опубликована: Янв. 13, 2017
Tau
pathology
in
AD
spreads
a
hierarchical
pattern,
whereby
it
first
appears
the
entorhinal
cortex,
then
to
hippocampus
and
later
surrounding
areas.
Based
on
this
sequential
appearance,
can
be
classified
into
six
stages
("Braak
stages").
The
mechanisms
agents
underlying
progression
of
are
matter
debate.
Emerging
evidence
indicates
that
propagation
may
due
transmission
protein,
but
pathways
species
not
well
understood.
In
study
we
investigated
question
spreading
via
small
extracellular
vesicles
called
exosomes.Exosomes
from
different
sources
were
analyzed
by
biochemical
methods
electron
microscopy
(EM)
cryo-EM.
Microfluidic
devices
allow
culture
cell
populations
compartments
used
investigate
Tau.We
show
protein
is
released
cultured
primary
neurons
or
N2a
cells
overexpressing
constructs
exosomes.
Neuron-derived
exosomal
hypo-phosphorylated,
compared
with
cytosolic
Tau.
Depolarization
promotes
release
Tau-containing
exosomes,
highlighting
importance
neuronal
activity.
Using
microfluidic
exosomes
mediate
trans-neuronal
transfer
depending
synaptic
connectivity.
achieved
direct
between
neurons.
organotypic
hippocampal
slices,
conditioned
medium
taken
up
microglia,
astrocytes.
cells,
assemblies
They
induce
inclusions
other
molecules
expressing
mutant
human
We
also
studied
cerebrospinal
fluid
control
subjects
containing
monomeric
oligomeric
Split-luciferase
complementation
reveals
CSF
promote
aggregation
cells.Our
demonstrates
contribute
trans-synaptic
transmission,
thus
offer
new
approches
tauopathies.
Cold Spring Harbor Perspectives in Medicine,
Год журнала:
2012,
Номер
2(6), С. a006262 - a006262
Опубликована: Фев. 21, 2012
Colin
L.
Masters1
and
Dennis
J.
Selkoe2
The
Mental
Health
Research
Institute,
University
of
Melbourne,
Parkville
3010,
Australia
Center
for
Neurologic
Diseases,
Harvard
Medical
School
Brigham
Women's
Hospital,
Boston,
Massachusetts
02115
Correspondence:
c.masters{at}unimelb.edu.au
