Sex-specific gene exacerbates Parkinson's disease in male mice

Sex-specific gene exacerbates Parkinson's disease in male mice

In Parkinson’s disease (PD), progressive degeneration of dopamine-producing neurons in the brain’s substantia nigra region leads to gradual decline of voluntary movement control. While the cause of DA cell loss in PD is unknown, male sex is a strong risk factor. 

Males are twice as likely as females to develop PD, and men with PD progress more rapidly and experience greater neuronal degeneration than female counterparts. The authors previously showed that the Y-chromosome gene, SRY, directly regulates adult brain function in males independent of gonadal hormone influence. SRY protein colocalizes with DA neurons in the male substantia nigra, where it regulates DA biosynthesis and voluntary movement.

Researchers report that SRY, a Y-chromosome gene found only in males, may represent a genetic mechanism that exacerbates PD risk factors and disease progression in men.

In contrast to the theory that sex differences in PD stem solely from estrogen’s neuroprotective role in females, the authors found using human cell cultures and mouse models that SRY is aberrantly up-regulated in male substantia nigra, where the gene mediates motor control via dopamine biosynthesis.

In addition, the authors demonstrate that lowering SRY expression with antisense oligonucleotides in male rats in 6-hydroxydopamine (6-OHDA)-induced and rotenone-induced rat PD models mitigates key male biases, including neuronal degeneration and inflammation.  The protective effect of the SRY 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 SRY 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 SRY directly contributes to the sex differences in PD. 

The findings suggest that SRY represents a sex-specific mechanism for dopamine neuron death in men, according to the authors.