Loss of aromatase cytochrome P450 function as a risk factor for Parkinson's disease?
The final step in the physiological synthesis of 17beta estradiol (E(2)) is aromatization of precursor testosterone by a CYP19 gene product, cytochrome P450 estrogen aromatase in the C19 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 P450 aromatase as determining factor for PD vulnerability may unravel new avenues for the understanding and development of novel therapeutic approaches for Parkinson's disease.
OASI Institute for Research and Care on Mental Retardation and Brain Aging (IRCCS), Neuropharmacology Section, 94018 Troina, Italy.
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Morale
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L'Episcopo
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Tirolo
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Giaquinta
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Caniglia
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Testa
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Arcieri
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Serra
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Lupo
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Alberghina
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Harada
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Honda
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Panzica
Bianca
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Marchetti
D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D004781:Environmental Exposure; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D012307:Risk Factors
D004958:Estradiol; D001141:Aromatase