Woehlbier Ute, Colombo Alicia, Saaranen Mirva J, Pérez Viviana, Ojeda Jorge, Bustos Fernando J, Andreu Catherine I, Torres Mauricio, Valenzuela Vicente, Medinas Danilo B, Rozas Pablo, Vidal Rene L, Lopez-Gonzalez Rodrigo, Salameh Johnny, Fernandez-Collemann Sara, Muñoz Natalia, Matus Soledad, Armisen Ricardo, Sagredo Alfredo, Palma Karina, Irrazabal Thergiory, Almeida Sandra, Gonzalez-Perez Paloma, Campero Mario, Gao Fen-Biao, Henny Pablo, van Zundert Brigitte, Ruddock Lloyd W, Concha Miguel L, Henriquez Juan P, Brown Robert H, Hetz Claudio
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile Center for Genomics and Bioinformatics, Universidad Mayor, Santiago, Chile.
Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile Department of Pathological Anatomy, Hospital Clínico, University of Chile, Santiago, Chile.
EMBO J. 2016 Apr 15;35(8):845-65. doi: 10.15252/embj.201592224. Epub 2016 Feb 11.
Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease.
内质网（ER）蛋白稳态紊乱是肌萎缩侧索硬化症（ALS）的一个常见特征。蛋白二硫键异构酶（PDIs）是被鉴定为可能的ALS生物标志物以及神经保护因子的内质网折叠酶。然而，尚无功能研究探讨它们对疾病进程的影响。在此，我们对最近在两个主要的PDI基因PDIA1和PDIA3/ERp57中鉴定出的四种与ALS相关的突变进行了功能表征。斑马鱼中的表型筛选显示，这些PDI变体的表达会诱导与运动神经元连接中断相关的运动缺陷。同样，突变型PDIs的表达在运动神经元细胞培养模型中损害了树突生长。细胞和生化研究确定了这些PDI突变体致病性背后不同的分子缺陷。最后，在神经系统中靶向ERp57会导致小鼠出现严重的运动功能障碍，并伴有神经肌肉突触的丧失。这项研究确定内质网蛋白稳态失衡是ALS的一个危险因素，驱动疾病的初始阶段。
