Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan; Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Neuroscience. 2019 Aug 21;414:128-140. doi: 10.1016/j.neuroscience.2019.06.026. Epub 2019 Jul 5.
Tay-Sachs disease (TSD) is a GM2 gangliosidosis lysosomal storage disease caused by a loss of lysosomal hexosaminidase-A (HEXA) activity and characterized by progressive neurodegeneration due to the massive accumulation of GM2 ganglioside in the brain. Here, we generated iPSCs derived from patients with TSD, and found similar potential for neural differentiation between TSD-iPSCs and normal iPSCs, although neural progenitor cells (NPCs) derived from the TSD-iPSCs exhibited enlarged lysosomes and upregulation of the lysosomal marker, LAMP1, caused by the accumulation of GM2 ganglioside. The NPCs derived from TSD-iPSCs also had an increased incidence of oxidative stress-induced cell death. TSD-iPSC-derived neurons showed a decrease in exocytotic activity with the accumulation of GM2 ganglioside, suggesting deficient neurotransmission in TSD. Our findings demonstrated that NPCs and mature neurons derived from TSD-iPSCs are potentially useful cellular models of TSD and are useful for investigating the efficacy of drug candidates in the future.
泰萨二氏病（TSD）是一种 GM2 神经节苷脂贮积病，由溶酶体己糖胺酶-A（HEXA）活性丧失引起，其特征是由于 GM2 神经节苷脂在大脑中的大量积累导致进行性神经退行性变。在这里，我们从 TSD 患者中生成了 iPSCs，并发现 TSD-iPSCs 和正常 iPSCs 之间具有相似的神经分化潜力，尽管源自 TSD-iPSCs 的神经祖细胞（NPCs）由于 GM2 神经节苷脂的积累而显示出增大的溶酶体和溶酶体标记物 LAMP1 的上调。源自 TSD-iPSCs 的 NPCs 也具有增加的氧化应激诱导细胞死亡的发生率。TSD-iPSC 衍生的神经元显示出随着 GM2 神经节苷脂的积累而出现的胞吐作用活性降低，表明 TSD 中的神经传递缺陷。我们的研究结果表明，源自 TSD-iPSCs 的 NPCs 和成熟神经元是 TSD 的潜在有用的细胞模型，并且将来可用于研究候选药物的疗效。
