Sex-specific neuroprotection by inhibition of the Y-chromosome gene, <i>SRY</i>, in experimental Parkinson's disease.

Abstract

Parkinson's disease (PD) is a debilitating neurodegenerative disorder caused by the loss of midbrain dopamine (DA) neurons. While the cause of DA cell loss in PD is unknown, male sex is a strong risk factor. Aside from the protective actions of sex hormones in females, emerging evidence suggests that sex-chromosome genes contribute to the male bias in PD. We previously showed that the Y-chromosome gene, <i>SRY</i>, directly regulates adult brain function in males independent of gonadal hormone influence. <i>SRY</i> protein colocalizes with DA neurons in the male substantia nigra, where it regulates DA biosynthesis and voluntary movement. Here we demonstrate that nigral <i>SRY</i> expression is highly and persistently up-regulated in animal and human cell culture models of PD. Remarkably, lowering nigral <i>SRY</i> expression with antisense oligonucleotides in male rats diminished motor deficits and nigral DA cell loss in 6-hydroxydopamine (6-OHDA)-induced and rotenone-induced rat models of PD. The protective effect of the <i>SRY</i> antisense oligonucleotides was associated with male-specific attenuation of DNA damage, mitochondrial degradation, and neuroinflammation in the toxin-induced rat models of PD. Moreover, reducing nigral <i>SRY</i> expression diminished or removed the male bias in nigrostriatal degeneration, mitochondrial degradation, DNA damage, and neuroinflammation in the 6-OHDA rat model of PD, suggesting that <i>SRY</i> directly contributes to the sex differences in PD. These findings demonstrate that <i>SRY</i> directs a previously unrecognized male-specific mechanism of DA cell death and suggests that suppressing nigral Sry synthesis represents a sex-specific strategy to slow or prevent DA cell loss in PD.