Neuroprotective role for RORA in Parkinson’s disease revealed by analysis of post-mortem brain and a dopaminergic cell line

Parkinson’s disease (PD) is almost twice as prevalent in men, which has largely been attributed to the neuroprotective effect of oestradiol in women. RORA (retinoic acid receptor-related orphan receptor alpha) regulates the transcription of central aromatase, the enzyme responsible for local oestradiol synthesis, and RORA expression is regulated by sex hormones. Moreover, RORA protects neurons against oxidative stress, a key mechanism contributing to the loss of dopaminergic neurones in PD. We hypothesized that there would be sex differences in RORA expression in the substantia nigra pars compacta (SNpc), which could contribute to sex differences observed in PD prevalence and pathogenesis. In a case-control study, qPCR and western blot analyses quantified gene and protein expression in the SNpc of post-mortem brains (n = 14 late-stage PD and 11 age- and sex-matched controls). The neuroprotective properties of a RORA agonist were then investigated using a dopaminergic cell culture toxin-based model of PD with measures of viability, mitochondrial function and apoptosis. RORA was expressed at significantly higher levels in the SNpc from control females compared to males. In PD, we found differential changes in SNpc RORA expression by sex. Treatment with a RORA agonist showed significant neuroprotection in our cell culture model of PD and revealed significant effects on intracellular redox involved in neuronal survival and demise. This is the first demonstration of a sex-specific pattern of RORA protein and gene expression in the human SNpc that is differentially altered in male and female PD subjects, supporting a role for RORA in sex-specific aspects of PD. Furthermore, our in vitro PD model indicates mechanisms whereby a RORA agonist exerts its neuroprotective effect, highlighting the translational potential for RORA in PD.