Neurophysiopathology Unit.
Ann Neurol. 2015 Apr;77(4):697-709. doi: 10.1002/ana.24372. Epub 2015 Mar 13.
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease whose pathophysiological deficits, causing impairment in motor function, are largely unknown. Here we propose that hydrogen sulfide (H2 S), as a glial-released inflammatory factor, contributes to ALS-mediated motor neuron death.
H2 S concentrations were analyzed in the cerebrospinal fluid of 37 sporadic ALS patients and 14 age- and gender-matched controls, in tissues of a familial ALS (fALS) mouse model, and in spinal cord culture media by means of a specific and innovative high-performance liquid chromatography method. The effects of H2 S on motor neurons cultures was analyzed immunohistochemically and by patch clamp recordings and microfluorometry.
We found a significantly high level of H2 S in the spinal fluid of the ALS patients. Consistently, we found increased levels of H2 S in the tissues and in the media from mice spinal cord cultures bearing the fALS mutation SOD1G93A. In addition, NaHS, an H2 S donor, added to spinal culture, obtained from control C57BL/6J mice, is toxic for motor neurons, and induces an intracellular Ca(2+) increase, attenuated by the intracytoplasmatic application of adenosine triphosphate. We further show that H2 S is mainly released by astrocytes and microglia.
This study unravels H2 S as an astroglial mediator of motor neuron damage possibly involved in the cellular death characterizing ALS.
肌萎缩侧索硬化症（ALS）是一种运动神经元疾病，其病理生理缺陷导致运动功能障碍，但很大程度上尚不清楚。在这里，我们提出，作为一种胶质细胞释放的炎症因子，硫化氢（H2S）可能导致 ALS 介导的运动神经元死亡。
采用一种特定的创新高效液相色谱法，分析了 37 例散发性 ALS 患者和 14 名年龄和性别匹配的对照者的脑脊液、家族性 ALS（fALS）小鼠模型组织和脊髓培养液中的 H2S 浓度。通过免疫组织化学和膜片钳记录及微荧光法分析 H2S 对运动神经元培养物的影响。
我们发现 ALS 患者的脑脊液中 H2S 水平明显升高。一致地，我们发现携带 fALS 突变 SOD1G93A 的小鼠组织和脊髓培养液中 H2S 水平升高。此外，在从对照 C57BL/6J 小鼠中获得的脊髓培养物中添加 H2S 供体 NaHS 对运动神经元有毒，并诱导细胞内 Ca2+增加，该增加可被三磷酸腺苷的细胞质内应用所减弱。我们进一步表明，H2S 主要由星形胶质细胞和小胶质细胞释放。
本研究揭示了 H2S 作为运动神经元损伤的星形胶质细胞介质，可能参与了 ALS 特征性的细胞死亡。
