Institute of Neuroscience, Soochow University, Suzhou 215123, China; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
Institute of Neuroscience, Soochow University, Suzhou 215123, China; Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Brain Behav Immun. 2018 Jan;67:77-90. doi: 10.1016/j.bbi.2017.07.159. Epub 2017 Aug 1.
Hydrogen sulfide (HS), a novel neuromodulator, is linked to the pathogenesis of several neurodegenerative disorders. Exogenous application of HS exerts neuroprotection via anti-inflammation and anti-oxidative stress in animal and cellular models of Parkinson's disease (PD). However, the role of endogenous HS and the contribution of its various synthases in PD remain unclear. In the present study, we found a decline of plasma and striatal sulfide level in 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mouse model. Interestingly, among the three HS generating enzymes, only cystathionine β-synthase (CBS) expression was largely reduced in the striatum of MPTP-treated mice. The in vitro study confirmed a significant decrease of CBS expression in 1-methyl-4-phenylpyridinium (MPP)-stimulated astrocytes and microglia, but not in neurons or SH-SY5Y dopaminergic cells. Striatal CBS overexpression, elicited by stereotaxic delivery with Cbs gene using recombinant adeno-associated-virus (rAAV-Cbs), successfully enhanced the sulfide level in the striatum and partially rescued the MPTP-induced dopaminergic neurotoxicity in the midbrain. Specifically, striatal CBS overexpression alleviated the motor deficits and dopaminergic neuron losses in the nigro-striatal pathway, with a concomitant inhibition of glial activation in MPTP-treated mice. Furthermore, compared to rAAV-Vector, rAAV-Cbs injection reduced the aberrant accumulation of nitric oxide and 3-nitrotyrosine (an indicator of protein nitration) in the striatum of MPTP-treated mice. Notably, it also attenuated the increase of nitrated α-synuclein level in MPTP mice. The in vitro study demonstrated that lentivirus-mediated CBS overexpression elevated the sulfide generation in glial cells. Moreover, glial CBS overexpression offered protection to midbrain dopaminergic neurons through repressing nitric oxide overproduction in both glial and neuronal cells induced by MPP. Taken together, our data suggest that impaired CBS-HS axis may contribute to the pathogenesis of PD, and that modulation of this axis may become a novel therapeutic approach for PD.
硫化氢（HS）是一种新型的神经调质，与几种神经退行性疾病的发病机制有关。在帕金森病（PD）的动物和细胞模型中，外源性 HS 的应用通过抗炎和抗氧化应激发挥神经保护作用。然而，内源性 HS 的作用及其各种合酶在 PD 中的贡献仍不清楚。在本研究中，我们发现 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型中血浆和纹状体硫化物水平下降。有趣的是，在三种产生 HS 的酶中，只有胱硫醚-β-合酶（CBS）在 MPTP 处理的小鼠纹状体中的表达大量减少。体外研究证实，1-甲基-4-苯基吡啶（MPP）刺激的星形胶质细胞和小胶质细胞中 CBS 表达显著下降，但神经元或 SH-SY5Y 多巴胺能细胞中没有。纹状体 CBS 的过表达，通过使用重组腺相关病毒（rAAV-Cbs）进行立体定向传递 Cbs 基因来诱导，成功地增加了纹状体中的硫化物水平，并部分挽救了 MPTP 诱导的中脑多巴胺能神经毒性。具体而言，纹状体 CBS 的过表达减轻了黑质纹状体通路中的运动缺陷和多巴胺能神经元丢失，并伴有 MPTP 处理小鼠中胶质细胞激活的抑制。此外，与 rAAV-载体相比，rAAV-Cbs 注射减少了 MPTP 处理小鼠纹状体中一氧化氮和 3-硝基酪氨酸（一种蛋白质硝化的指标）的异常积累。值得注意的是，它还减轻了 MPTP 小鼠中硝化α-突触核蛋白水平的增加。体外研究表明，慢病毒介导的 CBS 过表达增加了胶质细胞中的硫化物生成。此外，胶质细胞 CBS 的过表达通过抑制 MPP 诱导的胶质细胞和神经元细胞中一氧化氮的过度产生，为中脑多巴胺能神经元提供了保护。总之，我们的数据表明，CBS-HS 轴的损伤可能导致 PD 的发病机制，并且调节该轴可能成为 PD 的一种新的治疗方法。
