University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children’s Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, 9500 Gilman Dr, La Jolla, CA 92093, MC 0695, USA.
Hum Mol Genet. 2011 Sep 15;20(18):3642-52. doi: 10.1093/hmg/ddr284. Epub 2011 Jun 17.
Amyotrophic lateral sclerosis (ALS) is an incurable neuromuscular disease that leads to a profound loss of life quality and premature death. Around 10% of the cases are inherited and ALS8 is an autosomal dominant form of familial ALS caused by mutations in the vamp-associated protein B/C (VAPB) gene. The VAPB protein is involved in many cellular processes and it likely contributes to the pathogenesis of other forms of ALS besides ALS8. A number of successful drug tests in ALS animal models could not be translated to humans underscoring the need for novel approaches. The induced pluripotent stem cells (iPSC) technology brings new hope, since it can be used to model and investigate diseases in vitro. Here we present an additional tool to study ALS based on ALS8-iPSC. Fibroblasts from ALS8 patients and their non-carrier siblings were successfully reprogrammed to a pluripotent state and differentiated into motor neurons. We show for the first time that VAPB protein levels are reduced in ALS8-derived motor neurons but, in contrast to over-expression systems, cytoplasmic aggregates could not be identified. Our results suggest that optimal levels of VAPB may play a central role in the pathogenesis of ALS8, in agreement with the observed reduction of VAPB in sporadic ALS.
肌萎缩侧索硬化症（ALS）是一种无法治愈的神经肌肉疾病，会导致生活质量的严重下降和过早死亡。大约 10%的病例是遗传性的，ALS8 是一种常染色体显性形式的家族性 ALS，由 vamp 相关蛋白 B/C（VAPB）基因的突变引起。VAPB 蛋白参与许多细胞过程，它可能除了 ALS8 之外，还与其他形式的 ALS 的发病机制有关。许多在 ALS 动物模型中成功的药物试验不能转化为人类，这突显了需要新的方法。诱导多能干细胞（iPSC）技术带来了新的希望，因为它可以用于体外模拟和研究疾病。在这里，我们提出了一种基于 ALS8-iPSC 的研究 ALS 的附加工具。来自 ALS8 患者及其非携带者兄弟姐妹的成纤维细胞被成功地重编程为多能状态，并分化为运动神经元。我们首次证明，VAPB 蛋白水平在 ALS8 衍生的运动神经元中降低，但与过表达系统不同，不能识别细胞质聚集物。我们的结果表明，VAPB 的最佳水平可能在 ALS8 的发病机制中起核心作用，这与在散发性 ALS 中观察到的 VAPB 减少一致。
