Department of Stem Cell Biology (former IZKF junior research group III), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Max-Planck Institute of Psychiatry, Munich, Germany.
Hum Mol Genet. 2019 Mar 15;28(6):961-971. doi: 10.1093/hmg/ddy397.
Spastic paraplegia gene 11(SPG11)-linked hereditary spastic paraplegia is a complex monogenic neurodegenerative disease that in addition to spastic paraplegia is characterized by childhood onset cognitive impairment, thin corpus callosum and enlarged ventricles. We have previously shown impaired proliferation of SPG11 neural progenitor cells (NPCs). For the delineation of potential defect in SPG11 brain development we employ 2D culture systems and 3D human brain organoids derived from SPG11 patients' iPSC and controls. We reveal that an increased rate of asymmetric divisions of NPCs leads to proliferation defect, causing premature neurogenesis. Correspondingly, SPG11 organoids appeared smaller than controls and had larger ventricles as well as thinner germinal wall. Premature neurogenesis and organoid size were rescued by GSK3 inhibititors including the Food and Drug Administration-approved tideglusib. These findings shed light on the neurodevelopmental mechanisms underlying disease pathology.
痉挛性截瘫基因 11（SPG11）相关性遗传性痉挛性截瘫是一种复杂的单基因神经退行性疾病，除痉挛性截瘫外，还以儿童期发病的认知障碍、胼胝体变薄和脑室增大为特征。我们之前已经证明 SPG11 神经祖细胞（NPC）的增殖受损。为了描绘 SPG11 大脑发育的潜在缺陷，我们使用二维培养系统和源自 SPG11 患者 iPSC 和对照的 3D 人脑类器官。我们揭示 NPC 不对称分裂率的增加导致增殖缺陷，从而导致过早的神经发生。相应地，SPG11 类器官比对照类器官小，并且脑室更大，生发壁更薄。通过包括美国食品和药物管理局批准的 tideglusib 在内的 GSK3 抑制剂可以挽救过早的神经发生和类器官大小。这些发现为疾病发病机制的神经发育机制提供了线索。
