Taniguchi-Ikeda Mariko, Koyanagi-Aoi Michiyo, Maruyama Tatsuo, Takaori Toru, Hosoya Akiko, Tezuka Hiroyuki, Nagase Shotaro, Ishihara Takuma, Kadoshima Taisuke, Muguruma Keiko, Ishigaki Keiko, Sakurai Hidetoshi, Mizoguchi Akira, Novitch Bennett G, Toda Tatsushi, Watanabe Momoko, Aoi Takashi
Department of Clinical Genetics, Fujita Health University Hospital, 1-98 Dengakugakubo, Kutsukake-chou, Toyoake, Aichi 470-1192, Japan.
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
iScience. 2021 Sep 17;24(10):103140. doi: 10.1016/j.isci.2021.103140. eCollection 2021 Oct 22.
Fukuyama congenital muscular dystrophy (FCMD) is a severe, intractable genetic disease that affects the skeletal muscle, eyes, and brain and is attributed to a defect in alpha dystroglycan (αDG) -mannosyl glycosylation. We previously established disease models of FCMD; however, they did not fully recapitulate the phenotypes observed in human patients. In this study, we generated induced pluripotent stem cells (iPSCs) from a human FCMD patient and differentiated these cells into three-dimensional brain organoids and skeletal muscle. The brain organoids successfully mimicked patient phenotypes not reliably reproduced by existing models, including decreased αDG glycosylation and abnormal radial glial (RG) fiber migration. The basic polycyclic compound Mannan-007 (Mn007) restored αDG glycosylation in the brain and muscle models tested and partially rescued the abnormal RG fiber migration observed in cortical organoids. Therefore, our study underscores the importance of αDG -mannosyl glycans for normal RG fiber architecture and proper neuronal migration in corticogenesis.
福山型先天性肌营养不良（FCMD）是一种严重的、难治性的遗传病，会影响骨骼肌、眼睛和大脑，其病因是α- dystroglycan（αDG）-甘露糖基糖基化缺陷。我们之前建立了FCMD的疾病模型；然而，它们并未完全重现人类患者中观察到的表型。在本研究中，我们从一名人类FCMD患者中生成了诱导多能干细胞（iPSC），并将这些细胞分化为三维脑类器官和骨骼肌。脑类器官成功模拟了现有模型无法可靠再现的患者表型，包括αDG糖基化降低和放射状胶质（RG）纤维迁移异常。碱性多环化合物Mannan - 007（Mn007）在测试的脑和肌肉模型中恢复了αDG糖基化，并部分挽救了在皮质类器官中观察到的异常RG纤维迁移。因此，我们的研究强调了αDG -甘露糖基聚糖对于皮质发生过程中正常RG纤维结构和神经元正常迁移的重要性。
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