Study Rationale:
Parkinson’s disease (PD) is more common in men than in women, and men with PD exhibit earlier onset, faster progression, more severe motor symptoms and more frequent cognitive decline. However, most PD studies do not take into account the influence of sex on the disease; the cause of these sex differences therefore remains unknown. Female sex hormones improve PD symptoms in both men and women and also modulate production of melanin in the skin. We recently reported that excessive, age-dependent production of melanin in the brain — so-called neuromelanin — can trigger PD pathology, a mechanism that could explain these sex differences.
Hypothesis:
We hypothesize that the male bias in PD may be due to a greater or accelerated age-dependent production of neuromelanin in men compared to women; this accumulation would allow men to reach damaging and potentially PD-triggering levels of intracellular neuromelanin faster or more frequently than women.
Study Design:
Our hypothesis will be experimentally tested using the only preclinical model currently available that exhibits age-dependent neuromelanin production within PD-vulnerable neurons, at concentrations up to those reached in elderly humans. This model, which we developed, shows major PD features in parallel with the progressive accumulation of neuromelanin. We will therefore use this model to determine whether differential neuromelanin levels in males versus females are associated with differences in PD onset, disease progression and disease severity. We will also assess whether manipulating sex hormones, via genetic or pharmacological means, can modulate intracellular neuromelanin levels and modify PD pathology in this model.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Sex-based strategies for modulating neuromelanin levels may provide unprecedented therapeutic opportunities to prevent, halt or delay neuronal dysfunction and degeneration linked to both PD and brain aging.
Next Steps for Development:
The elucidation of mechanisms underlying sex differences in PD should provide novel tools for the treatment or prevention of PD that can be adapted to specific risk populations.