Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
PLoS One. 2010 Dec 9;5(12):e15307. doi: 10.1371/journal.pone.0015307.
Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, and recent evidence has suggested that endoplasmic reticulum (ER) stress signaling is involved in the pathogenesis of ALS. Here we identified a small molecule, SUN N8075, which has a marked protective effect on ER stress-induced cell death, in an in vitro cell-based screening, and its protective mechanism was mediated by an induction of VGF nerve growth factor inducible (VGF): VGF knockdown with siRNA completely abolished the protective effect of SUN N8075 against ER-induced cell death, and overexpression of VGF inhibited ER-stress-induced cell death. VGF level was lower in the spinal cords of sporadic ALS patients than in the control patients. Furthermore, SUN N8075 slowed disease progression and prolonged survival in mutant SOD1 transgenic mouse and rat models of ALS, preventing the decrease of VGF expression in the spinal cords of ALS mice. These data suggest that VGF plays a critical role in motor neuron survival and may be a potential new therapeutic target for ALS, and SUN N8075 may become a potential therapeutic candidate for treatment of ALS.
肌萎缩侧索硬化症（ALS）是最常见的成人发病运动神经元病，最近的证据表明内质网（ER）应激信号参与了 ALS 的发病机制。在这里，我们在体外细胞筛选中鉴定出一种小分子 SUN N8075，它对 ER 应激诱导的细胞死亡具有显著的保护作用，其保护机制是通过诱导 VGF 神经生长因子诱导（VGF）介导的：用 siRNA 敲低 VGF 完全消除了 SUN N8075 对 ER 诱导的细胞死亡的保护作用，而过表达 VGF 抑制了 ER 应激诱导的细胞死亡。散发性 ALS 患者脊髓中的 VGF 水平低于对照患者。此外，SUN N8075 减缓了突变型 SOD1 转基因小鼠和大鼠 ALS 模型中的疾病进展并延长了生存期，防止了 ALS 小鼠脊髓中 VGF 表达的下降。这些数据表明 VGF 在运动神经元存活中起关键作用，可能是 ALS 的一个潜在新治疗靶点，SUN N8075 可能成为治疗 ALS 的潜在治疗候选药物。
