Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, PR China.
Neuroscience. 2010 Jan 20;165(2):455-62. doi: 10.1016/j.neuroscience.2009.10.042.
Synphilin-1 is a cytoplasmic protein with unclear function. Synphilin-1 has been identified as an interaction partner of alpha-synuclein. The interaction between synphilin-1 and alpha-synuclein has implications in Parkinson's disease. In this study, we stably overexpressed human synphilin-1 in mouse N1E-115 neuroblastoma cells. We found that overexpression of synphilin-1 shortened cell growth doubling time and increased neurite outgrowth. Knockdown of endogenous synphilin-1 caused neuronal toxicity and shortened neurite outgrowth. We further found that synphilin-1 increased activation of the extracellular signal-regulated kinases (ERK1/2) and mediated neurite outgrowth. Rotenone, mitochondrial complex I inhibitor, has been shown previously to induce dopaminergic neurodegeneration and Parkinsonism in rats and Drosophila. We found that Rotenone induced apoptotic cell death in N1E-115 cells via caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage. Overexpression of synphilin-1 significantly reduced Rotenone-induced cell death, caspase-3 activation and PARP cleavage. The results indicate that synphilin-1 displays trophic and protective effects in vitro, suggesting that synphilin-1 may play a protective role in Parkinson's disease (PD) pathogenesis and may lead to a potential therapeutic target for PD intervention.
突触核蛋白 1 是一种细胞质蛋白，其功能尚不清楚。突触核蛋白 1 已被鉴定为α-突触核蛋白的相互作用伙伴。突触核蛋白 1 与α-突触核蛋白之间的相互作用与帕金森病有关。在这项研究中，我们在小鼠 N1E-115 神经母细胞瘤细胞中稳定过表达人突触核蛋白 1。我们发现，突触核蛋白 1 的过表达缩短了细胞生长倍增时间并增加了轴突生长。内源性突触核蛋白 1 的敲低导致神经元毒性并缩短了轴突生长。我们进一步发现，突触核蛋白 1 增加了细胞外信号调节激酶 (ERK1/2) 的激活并介导了轴突生长。鱼藤酮，线粒体复合物 I 抑制剂，先前已被证明可在大鼠和果蝇中诱导多巴胺能神经退行性变和帕金森病。我们发现鱼藤酮通过半胱天冬酶-3 激活和多聚（ADP-核糖）聚合酶 (PARP) 切割诱导 N1E-115 细胞凋亡性细胞死亡。突触核蛋白 1 的过表达显著降低了鱼藤酮诱导的细胞死亡、半胱天冬酶-3 激活和 PARP 切割。结果表明，突触核蛋白 1 在体外具有营养和保护作用，表明突触核蛋白 1 可能在帕金森病 (PD) 发病机制中发挥保护作用，并可能成为 PD 干预的潜在治疗靶点。
