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Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model.
[phenylketonuria]
Phenylketonuria
(
PKU
)
,
if
not
detected
and
treated
in
newborns
,
causes
severe
neurological
dysfunction
and
cognitive
and
behavioral
deficiencies
.
Despite
the
biochemical
characterization
of
PKU
,
the
molecular
mechanisms
underlying
PKU
-associated
brain
dysfunction
remain
poorly
understood
.
The
aim
of
this
study
was
to
gain
insights
into
the
pathogenesis
of
this
neurological
damage
by
analyzing
protein
expression
profiles
in
brain
tissue
of
Black
and
Tan
BRachyury-PahEnu
2
mice
(
a
mouse
model
of
PKU
)
.
We
compared
the
cerebral
protein
expression
of
homozygous
PKU
mice
with
that
of
their
heterozygous
counterparts
using
two
-dimensional
difference
gel
electrophoresis
analysis
,
and
identified
21
differentially
expressed
proteins
,
four
of
which
were
over-expressed
and
17
under-expressed
.
An
in
silico
bioinformatic
approach
indicated
that
protein
under-expression
was
related
to
neuronal
differentiation
and
dendritic
growth
,
and
to
such
neurological
disorders
as
progressive
motor
neuropathy
and
movement
disorders
.
Moreover
,
functional
annotation
analyses
showed
that
some
identified
proteins
were
involved
in
oxidative
metabolism
.
To
further
investigate
the
proteins
involved
in
the
neurological
damage
,
we
validated
two
of
the
proteins
that
were
most
strikingly
under-expressed
,
namely
,
Syn
2
and
Dpysl
2
,
which
are
involved
in
synaptic
function
and
neurotransmission
.
We
found
that
Glu
2
/
3
and
NR
1
receptor
subunits
were
over-expressed
in
PKU
mouse
brain
.
Our
results
indicate
that
differential
expression
of
these
proteins
may
be
associated
with
the
processes
underlying
PKU
brain
dysfunction
,
namely
,
decreased
synaptic
plasticity
and
impaired
neurotransmission
.
We
identified
a
set
of
proteins
whose
expression
is
affected
by
hyperphenylalaninemia
.
We
think
that
phenylketonuria
(
PKU
)
brain
dysfunction
also
depends
on
reduced
Syn
2
and
Dpysl
2
levels
,
increased
Glu
2
/
3
and
NR
1
levels
,
and
decreased
Pkm
,
Ckb
,
Pgam
1
and
Eno
1
levels
.
These
findings
finally
confirm
that
alteration
in
synaptic
function
,
in
transmission
and
in
energy
metabolism
underlie
brain
damage
provoked
by
hyperphenylalaninemias
.
Diseases
Validation
Diseases presenting
"namely"
symptom
hydrocephalus with stenosis of the aqueduct of sylvius
neonatal adrenoleukodystrophy
phenylketonuria
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