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Loss of aromatase cytochrome P450 function as a risk factor for Parkinson's disease?
[aromatase deficiency]
The
final
step
in
the
physiological
synthesis
of
17
beta
estradiol
(
E
(
2
)
)
is
aromatization
of
precursor
testosterone
by
a
CYP
19
gene
product
,
cytochrome
P
450
estrogen
aromatase
in
the
C
19
steroid
metabolic
pathway
.
Within
the
central
nervous
system
(
CNS
)
the
presence
,
distribution
,
and
activity
of
aromatase
have
been
well
characterized
.
Developmental
stage
and
injury
are
known
modulators
of
brain
enzyme
activity
,
where
both
neurons
and
glial
cells
reportedly
have
the
capability
to
synthesize
this
key
estrogenic
enzyme
.
The
gonadal
steroid
E
(
2
)
is
a
critical
survival
,
neurotrophic
and
neuroprotective
factor
for
dopaminergic
neurons
of
the
substantia
nigra
pars
compacta
(
SNpc
)
,
the
cells
that
degenerate
in
Parkinson
's
disease
(
PD
)
.
In
previous
studies
we
underlined
a
crucial
role
for
the
estrogenic
status
at
the
time
of
injury
in
dictating
vulnerability
to
the
parkinsonian
neurotoxin
1
-
methyl-
4
-
phenyl-
1
,
2
,
3
,
6
-
tetrahydropyridine
(
MPTP
)
.
Our
ongoing
studies
address
the
contribution
of
brain
aromatase
and
extragonadal
E
(
2
)
as
vulnerability
factors
for
PD
pathology
in
female
brain
,
by
exposing
aromatase
knockout
(
ArKO
,
-
/
-
)
female
mice
which
are
unable
to
synthesize
estrogens
to
MPTP
.
Our
initial
results
indicate
that
aromatase
deficiency
from
early
embryonic
life
significantly
impairs
the
functional
integrity
of
SNpc
tyrosine
hydroxylase
-
positive
neurons
and
dopamine
transporter
innervation
of
the
caudate-putamen
in
adulthood
.
In
addition
,
ArKO
females
exhibited
a
far
greater
vulnerability
to
MPTP-induced
nigrostriatal
damage
as
compared
to
their
Wt
type
gonadally
intact
and
gonadectomized
counterparts
.
Characterization
of
this
novel
implication
of
P
450
aromatase
as
determining
factor
for
PD
vulnerability
may
unravel
new
avenues
for
the
understanding
and
development
of
novel
therapeutic
approaches
for
Parkinson
's
disease
.
Diseases
Validation
Diseases presenting
"brain aromatase"
symptom
aromatase deficiency
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