Oestrogen Receptors and Signalling Pathways: Implications for Neuroprotective Effects of Sex Steroids in Parkinson's Disease

Parkinsons disease (PD) is an age-related neurodegenerative disorder with a higher incidence in the male population. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, 17 beta-oestradiol but not androgens were shown to protect dopamine (DA) neurones. We report that oestrogen receptors (ER)a and beta distinctly contribute to neuroprotection against MPTP toxicity, as revealed by examining the membrane DA transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and tyrosine hyroxylase in ER wild-type (WT) and knockout (ERKO) C57Bl/6 male mice. Intact ERKO beta mice had lower levels of striatal DAT and VMAT2, whereas ERKOa mice were the most sensitive to MPTP toxicity compared to WT and ERKO beta mice and had the highest levels of plasma androgens. In both ERKO mice groups, treatment with 17 beta-oestradiol did not provide neuroprotection against MPTP, despite elevated plasma 17 beta-oestradiol levels. Next, the recently described membrane G protein-coupled oestrogen receptor (GPER1) was examined in female Macaca fascicularis monkeys and mice. GPER1 levels were increased in the caudate nucleus and the putamen of MPTP-monkeys and in the male mouse striatum lesioned with methamphetamine or MPTP. Moreover, neuroprotective mechanisms in response to oestrogens transmit via Akt/glycogen synthase kinase-3 (GSK3) signalling. The intact and lesioned striata of 17 beta-oestradiol treated monkeys, similar to that of mice, had increased levels of pAkt (Ser 473)/beta III-tubulin, pGSK3 (Ser 9)/beta III-tubulin and Akt/beta III-tubulin. Hence, ERa, ER beta and GPER1 activation by oestrogens is imperative in the modulation of ER signalling and serves as a basis for evaluating nigrostriatal neuroprotection.