Brain and Gender Laboratory, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia;
Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3168, Australia.
Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16577-16582. doi: 10.1073/pnas.1900406116. Epub 2019 Aug 1.
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, , directly regulates adult brain function in males independent of gonadal hormone influence. protein colocalizes with DA neurons in the male substantia nigra, where it regulates DA biosynthesis and voluntary movement. Here we demonstrate that nigral expression is highly and persistently up-regulated in animal and human cell culture models of PD. Remarkably, lowering nigral 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 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 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 directly contributes to the sex differences in PD. These findings demonstrate that 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.
帕金森病（PD）是一种由中脑多巴胺（DA）神经元丧失引起的进行性神经退行性疾病。虽然 PD 中 DA 细胞丧失的原因尚不清楚，但男性性别是一个强烈的风险因素。除了女性性激素的保护作用外，新出现的证据表明，性染色体基因导致 PD 中男性偏倚。我们之前表明，Y 染色体基因， ，在不依赖性腺激素影响的情况下，直接调节雄性成年大脑功能。 蛋白与雄性黑质中的 DA 神经元共定位，在那里它调节 DA 生物合成和自主运动。在这里，我们证明在 PD 的动物和人类细胞培养模型中，黑质中的 表达高度且持续上调。值得注意的是，用反义寡核苷酸降低雄性大鼠黑质中的 表达可减轻 6-羟多巴胺（6-OHDA）诱导和鱼藤酮诱导的 PD 大鼠模型中的运动缺陷和黑质 DA 细胞丧失。 反义寡核苷酸的保护作用与毒素诱导的 PD 大鼠模型中 DNA 损伤、线粒体降解和神经炎症的雄性特异性减弱有关。此外，降低黑质中的 表达可减少或消除 6-OHDA 大鼠模型中黑质纹状体变性、线粒体降解、DNA 损伤和神经炎症的雄性偏倚，表明 直接导致 PD 中的性别差异。这些发现表明 指导了以前未被认识到的 DA 细胞死亡的雄性特异性机制，并表明抑制黑质 Sry 合成代表了一种减缓或预防 PD 中 DA 细胞丧失的性别特异性策略。
