Loss of aromatase cytochrome P450 function as a risk factor for Parkinson's disease?

Abstract

The final step in the physiological synthesis of 17β estradiol (E₂) 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 E₂ 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 E₂ 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.

Introduction

The female hormone, 17β estradiol (E₂), plays a fundamental role in a multitude of physiological processes in mammals, including reproduction, cardiovascular health, skeletal growth and bone homeostasis, immune and cognitive functions. Within the brain, E₂ plays a pivotal role in the regulation of neuron survival, differentiation and plasticity (McEwen and Alves, 1999, Garcia-Segura et al., 2001, Morris et al., 2004). One key aspect is represented by the critical action of E₂ in dictating gender-specific processes of brain development (Wilson and Davies, 2007). Indeed, the conversion of androgens to estrogens within the CNS is a critical means by which testosterone regulates many physiological and behavioural processes such as sexual differentiation of the brain (MacLusky and Naftolin, 1981). This critical step is performed by aromatase, a member of the P450 superfamily of cytochrome enzymes, and a product of the CYP19 gene (Roselli and Klosterman, 1998, Bakker et al., 2003). Unlike other P450 enzyme members, aromatase is the only one capable of creating an aromatic ring characterizing the estrogenic structure.

Aromatase is tissue-specifically regulated in various organs and cells and plays an important role through endocrine and intracrine estrogen synthesis (Harada et al., 1993, Honda et al., 1994, Simpson and Davis, 2001). Therefore aromatase deficiency causes crucial impairments of physiological functions in both gonadal and extragonadal tissues. In the CNS, aromatase has been shown to regulate neural plasticity by stimulating growth and migration of cells, protecting against degeneration and brain injury, regulating the reproductive endocrine axis, influencing learning and memory processes, stress and mood (Lephart et al., 2001). Of special interest, remarkable neuroprotective effects of brain aromatase have been demonstrated with respect to kainic acid excitotoxicity (Garcia-Segura et al., 1999), stroke (McCullough et al., 2003), Alzheimer's (ALZ) disease and epilepsy (Yue et al., 2005). In addition, polymorphisms in the CYP19 gene were shown to confer increased risk for ALZ pathology (Ivonen et al., 2004, Huang and Poduslo, 2006). While in normal conditions brain aromatase is almost exclusively localized in neurons, brain injury up-regulates this estrogenic enzymatic activity in astrocytes, and the implication of increased glial aromatase for neuroprotection has been highlighted in the studies of Garcia-Segura and collaborators (Garcia-Segura et al., 1999, Azcoitia et al., 2001, Garcia-Segura et al., 2001, Garcia-Ovejero et al., 2005).

In the brain, the abundance and activity of aromatase in rodents and humans have been well characterized (Lephart et al., 2001). In particular, aromatase-positive neurons have been localized within the lateral septal region, the bed nucleus of the stria terminalis, the hippocampus, the amygdala, several hypothalamic nuclei, the medial preoptic area, the nucleus accumbens, and several regions of the cortex, such as in the piriform lobe (Balthazart et al., 1991, Balthazart and Ball, 1998, Foidart and Harada, 1995, Jakab et al., 1994).

Aromatase has been also documented to participate in the physiological development of midbrain dopaminergic neurons in embryonic and early neonatal brain (Kipp et al., 2006). Indeed, E₂ is a specific physiological regulator of nigrostriatal dopaminergic neurons during development, in adulthood as well as during neuronal degenerative processes, such as Parkinson's disease (PD) (Beyer and Karolezak, 2000, Dluzen, 2000, Leranth et al., 2000, Grandbois et al., 2000, Kuppers et al., 2000, Dluzen and Horstink, 2003, D'Astous et al., 2004a, D'Astous et al., 2004b, Kipp et al., 2006, Morale et al., 2006), a progressive degenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Olanow et al., 2003).

In the present work, after a brief review of major risk and neuroprotective factors controlling vulnerability to PD, the evidence linking brain E₂ synthesis within the ventral midbrain and striatum will be reviewed and the hypothesis of brain aromatase deficiency as a risk factor for the vulnerability to PD pathology presented using a genetic approach, i.e. the aromatase knockout mouse strain, generated by Honda et al. (1998). Aromatase activity is sexually differentiated in mice during neonatal period as well as in adulthood (Bakker et al., 2004a, Bakker et al., 2004b) with higher testosterone-stimulated activity in males than in females. However, the neonatal female brain produces substantial amounts of estrogen that could play a significant role not only during the sexual differentiation of the female brain early in life (see Bakker et al., 2004a, Bakker et al., 2004b) but also later in life in modulating the future ability of brain cells to respond to brain injury (McCullough et al., 2003, Yue et al., 2005). Absence of aromatase activity in the brain and gonads of these ArKO mice (Bakker et al., 2004a, Bakker et al., 2004b) validates the ArKO mouse as a valuable tool in the study of the role of estradiol in modulating the vulnerability of nigrostriatal dopaminergic neurons to the environmental neurotoxin, MPTP.