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Phenylalanine reduces synaptic density in mixed cortical cultures from mice.
[classical phenylketonuria]
Classical
phenylketonuria
(
PKU
)
is
caused
by
deficiency
of
phenylalanine
hydroxylase
,
resulting
in
an
accumulation
of
its
upstream
metabolite
phenylalanine
in
brain
tissue
and
cerebrospinal
fluid
of
PKU
patients
.
PKU
is
neuropathologically
characterized
by
reduced
dendritic
arborization
,
loss
of
synapses
,
and
neurodegeneration
.
We
investigated
whether
increased
concentrations
of
phenylalanine
cause
reduced
synaptic
density
and
alter
dendritic
branching
.
We
treated
primary
cortical
neurons
differentiated
for
21
d
in
vitro
with
5
mM
phenylalanine
in
the
presence
of
all
essential
amino
acids
.
Immunocytochemical
analysis
of
12
and
21
d
in
vitro
primary
neurons
revealed
no
changes
of
dendritic
morphology
or
neuronal
viability
but
a
significant
difference
in
synaptic
density
,
suggesting
that
elevated
concentrations
of
extracellular
phenylalanine
cause
an
impairment
of
synaptogenesis
.
Although
impairment
of
cerebral
energy
metabolism
has
been
identified
as
an
important
pathophysiological
principal
in
many
diseases
,
respiratory
chain
function
has
not
been
extensively
studied
in
PKU
before
.
We
investigated
whether
phenylalanine
inhibits
respiratory
chain
complexes
I
-V
.
In
vitro
analysis
revealed
no
inhibitory
effect
of
phenylalanine
on
complexes
I
-V
,
but
an
inhibition
of
pyruvate
kinase
,
a
key
enzyme
of
glycolysis
,
catalyzing
the
formation
of
pyruvate
.
Pyruvate
kinase
is
part
of
the
enzyme
assay
to
investigate
enzyme
activity
of
mitochondrial
complex
V
and
it
remains
to
be
elucidated
whether
this
finding
is
relevant
in
vivo
.
In
conclusion
,
elevated
concentrations
of
phenylalanine
might
be
involved
in
mechanisms
underlying
impaired
synaptogenesis
in
PKU
,
supporting
the
common
therapeutic
strategy
to
reduce
phenylalanine
concentrations
in
the
brain
to
prevent
neurodegeneration
.
Diseases
Validation
Diseases presenting
"resulting in an accumulation of its upstream metabolite phenylalanine in brain tissue and cerebrospinal fluid of pku patients"
symptom
classical phenylketonuria
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