Modeling sex differences in human neurons

Sex differences in human dopaminergic neurons

Dopaminergic neurons are selectively vulnerable in Parkinson’s disease, which shows a strong and unexplained sex bias in incidence and progression. While hormonal influences are often proposed to explain this difference, increasing evidence suggests that neurons may also possess intrinsic sex-specific properties.

To directly test this idea, we use human induced pluripotent stem cells (iPSCs) to generate dopaminergic neurons with defined sex chromosome complements. Using unique isogenic cell lines derived from a mosaic XXY donor, we can generate genetically matched XX and XY neurons that share the same autosomal background. This system allows us to isolate the contribution of genetic sex from other sources of variability.

By comparing transcriptional profiles, dopamine physiology, and responses to cellular stress, we aim to determine whether sex chromosomes influence neuronal function and vulnerability. These studies provide a critical bridge between our genetic discoveries in model organisms and human neurodegenerative disease biology.