Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder worldwide. It is characterised by motor symptoms such as tremor, rigidity, and postural instability, along with a wide range of non-motor manifestations including depression, cognitive decline, autonomic dysfunction, and sleep disturbances. The neuropathological hallmark is the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), yet the precise mechanisms underlying this vulnerability remain unresolved.
After age, sex is the second greatest risk factor that predicts development of PD. Men are 2 times more likely to develop PD than women, tend to develop symptoms earlier, and follow more aggressive trajectories. Women often present with tremor-dominant forms, experience slower motor decline, but suffer greater burdens of depression, anxiety, and fatigue. Treatment outcomes, including responses to levodopa and the development of complications such as dyskinesia or dementia, also are also more likely to affect women.
The biological basis for these differences may involve either hormonal (testosterone, estrogen) or genetic (X, Y) mechanisms. In females, estrogen confers neuroprotective effects by enhancing mitochondrial function and reducing oxidative stress, whereas the male-specific SRY gene may be a vulnerability factor increasing dopamine cell death only in males.
Iron metabolism plays a pivotal role in the pathogenesis of PD. Excess iron in the SNc promotes oxidative stress and α-synuclein aggregation, while sex differences in systemic iron burden—lower in women until menopause—mirror epidemiological patterns of PD risk. Intriguingly, maternal iron deficiency disrupts expression of SRY activation during testis development, suggesting a potential link between iron biology and sex-specific vulnerability in PD.
We used in vitro dopamine cells lines to investigate if iron can regulate expression of SRY and to identify target genes that may contribute to sex-specific differences in PD. Recognising these differences is crucial for advancing towards personalised and equitable therapeutic strategies.