Zhai Jinbin, Zhang Lei, Mojsilovic-Petrovic Jelena, Jian Xiaoying, Thomas Jeffrey, Homma Kengo, Schmitz Anton, Famulok Michael, Ichijo Hidenori, Argon Yair, Randazzo Paul A, Kalb Robert G
Division of Pediatric Neurology and.
Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
J Neurosci. 2015 Jun 17;35(24):9088-105. doi: 10.1523/JNEUROSCI.5032-13.2015.
Mutant genes that underlie Mendelian forms of amyotrophic lateral sclerosis (ALS) and biochemical investigations of genetic disease models point to potential driver pathophysiological events involving endoplasmic reticulum (ER) stress and autophagy. Several steps in these cell biological processes are known to be controlled physiologically by small ADP-ribosylation factor (ARF) signaling. Here, we investigated the role of ARF guanine nucleotide exchange factors (GEFs), cytohesins, in models of ALS. Genetic or pharmacological inhibition of cytohesins protects motor neurons in vitro from proteotoxic insults and rescues locomotor defects in a Caenorhabditis elegans model of disease. Cytohesins form a complex with mutant superoxide dismutase 1 (SOD1), a known cause of familial ALS, but this is not associated with a change in GEF activity or ARF activation. ER stress evoked by mutant SOD1 expression is alleviated by antagonism of cytohesin activity. In the setting of mutant SOD1 toxicity, inhibition of cytohesin activity enhances autophagic flux and reduces the burden of misfolded SOD1. These observations suggest that targeting cytohesins may have potential benefits for the treatment of ALS.
导致孟德尔型肌萎缩侧索硬化症（ALS）的突变基因以及对遗传疾病模型的生化研究表明，内质网（ER）应激和自噬可能是驱动病理生理事件的潜在因素。已知这些细胞生物学过程中的几个步骤受小 ADP 核糖基化因子（ARF）信号通路的生理控制。在此，我们研究了 ARF 鸟嘌呤核苷酸交换因子（GEF）——细胞粘附素在 ALS 模型中的作用。对细胞粘附素进行基因或药理学抑制可在体外保护运动神经元免受蛋白毒性损伤，并挽救秀丽隐杆线虫疾病模型中的运动缺陷。细胞粘附素与突变型超氧化物歧化酶 1（SOD1）形成复合物，SOD1 是家族性 ALS 的已知病因，但这与 GEF 活性或 ARF 激活的变化无关。通过拮抗细胞粘附素活性可减轻突变型 SOD1 表达引起的内质网应激。在突变型 SOD1 毒性的情况下，抑制细胞粘附素活性可增强自噬通量并减轻错误折叠的 SOD1 的负担。这些观察结果表明，靶向细胞粘附素可能对 ALS 的治疗具有潜在益处。
