Sex-specific neuroprotection by inhibition of the Y-chromosome gene, SRY , in experimental Parkinson’s disease

Significance Parkinson’s disease (PD) is a progressive neurodegenerative disorder that results from the loss of midbrain dopamine neurons. While the cause of PD is unknown, male sex is one of the strongest risk factors. Traditionally, sex differences in PD have been attributed to the neuroprotective actions of estrogen in females. Here we show that the Y-chromosome gene, SRY , is up-regulated in animal and cell culture models of PD, and that suppressing SRY expression in male rats diminishes neurodegeneration and motor deficits in preclinical PD models. Taken together, our findings suggest that SRY up-regulation might be a potential pathogenic mechanism of male PD, and that SRY inhibition may be a novel male-specific strategy to slow or halt the progression of PD.