Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Department of Biomedical Laboratory Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0976, Japan.
Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
Stem Cell Reports. 2020 May 12;14(5):909-923. doi: 10.1016/j.stemcr.2020.03.012. Epub 2020 Apr 16.
GM1 gangliosidosis is a lysosomal storage disease caused by loss of lysosomal β-galactosidase activity and characterized by progressive neurodegeneration due to massive accumulation of GM1 ganglioside in the brain. Here, we generated induced pluripotent stem cells (iPSCs) derived from patients with GM1 gangliosidosis, and the resultant neurons showed impaired neurotransmitter release as a presynaptic function and accumulation of GM1 ganglioside. Treatment of normal neurons with GM1 ganglioside also disturbed presynaptic function. A high-content drug-screening system was then established and identified two compounds as drug candidates for GM1 gangliosidosis. Treatment of the patient-derived neurons with the candidate agents activated autophagy pathways, reducing GM1 ganglioside accumulation in vitro and in vivo, and restoring the presynaptic dysfunction. Our findings thus demonstrated the potential value of patient-derived iPSC lines as cellular models of GM1 gangliosidosis and revealed two potential therapeutic agents for future clinical application.
GM1 神经节苷脂贮积症是一种溶酶体贮积病，由溶酶体β-半乳糖苷酶活性丧失引起，其特征是由于 GM1 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，我们生成了源自 GM1 神经节苷脂贮积症患者的诱导多能干细胞（iPSC），由此产生的神经元表现出作为突触前功能的神经递质释放受损和 GM1 神经节苷脂的积累。GM1 神经节苷脂处理正常神经元也会扰乱突触前功能。然后建立了一个高通量药物筛选系统，并鉴定出两种化合物作为 GM1 神经节苷脂贮积症的候选药物。候选药物处理患者来源的神经元可激活自噬途径，减少 GM1 神经节苷脂在体外和体内的积累，并恢复突触前功能障碍。因此，我们的研究结果表明，源自患者的 iPSC 系作为 GM1 神经节苷脂贮积症的细胞模型具有潜在价值，并揭示了两种用于未来临床应用的潜在治疗药物。
