2种蛋白质共同引起致命性的神经系统疾病，本周发表在网络版《实验医学》（Experimental Medicine）期刊上的论文提出这一结论。
肌萎缩性脊髓侧索硬化症（ALS），即卢伽雷氏病，是一种破坏性的神经退行性疾病，引起运动功能丧失，最终导致死亡。90%以上的ALS病例没有已知的遗传原因或家族病史，然而，在一些患者中，脊髓细胞出现一种名为TDP-43蛋白质的异常积累。
卢伽雷病取名于患有此病的美国历史上著名棒球手Lou Gehrig，英国著名物理学家霍金也患有此病。
魁北克拉瓦尔大学的Jean-Pierre Julien 以及同事如今发现，ALS患者脊髓中TDP-43结合在一种称为NF-kB p65的炎症蛋白上，而在健康个体中这2种蛋白不结合。与健康个体相比，ALS患者脊髓中具有更丰富的TDP-43和p65，当两者相互作用时，一些蛋白因子被大量合成，并引起炎症反应和附近神经元的死亡。在小鼠ALS病例模型中，抑制P65活性的药剂治疗后能缓解神经元损伤和疾病症状。
这些发现突出了p65可作为神经衰退疾病的潜在的治疗靶点。（生物探索译）
相关英文论文摘要：
Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways
TDP-43 (TAR DNA-binding protein 43) inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). In this study, we report that TDP-43 and nuclear factor κB (NF-κB) p65 messenger RNA and protein expression is higher in spinal cords in ALS patients than healthy individuals. TDP-43 interacts with and colocalizes with p65 in glial and neuronal cells from ALS patients and mice expressing wild-type and mutant TDP-43 transgenes but not in cells from healthy individuals or nontransgenic mice. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-κB activity, reduced denervation in the neuromuscular junction and ALS disease symptoms. We propose that TDP-43 deregulation contributes to ALS pathogenesis in part by enhancing NF-κB activation and that NF-κB may constitute a therapeutic target for the disease.
英文论文链接: https://jem.rupress.org/content/early/2011/11/10/jem.20111313
