Periventricular neuronal heterotopia (PH) is one of the most common forms of cortical malformation in the human cortex. We show that human neuronal progenitor cells (hNPCs) derived from PH patients with a DCHS1 or FAT4 mutation as well as isogenic lines had altered migratory dynamics when grafted in the mouse brain. The affected migration was linked to altered autophagy as observed in vivo with an electron microscopic analysis of grafted hNPCs, a Western blot analysis of cortical organoids, and time-lapse imaging of hNPCs in the presence of bafilomycin A1. We further show that deficits in autophagy resulted in the accumulation of paxillin, a focal adhesion protein involved in cell migration. Strikingly, a single-cell RNA-seq analysis of hNPCs revealed similar expression levels of autophagy-related genes. Bolstering AMPK-dependent autophagy by metformin, an FDA-approved drug, promoted migration of PH patients-derived hNPCs. Our data indicate that transcription-independent homeostatic modifications in autophagy contributed to the defective migratory behavior of hNPCs in vivo and suggest that modulating autophagy in hNPCs might rescue neuronal migration deficits in some forms of PH.

中文翻译：

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二甲双胍可挽救脑室周围异位患者细胞的迁移缺陷

室周神经元异位（PH）是人类皮质中最常见的皮质畸形形式之一。我们发现，来自具有 DCHS1 或 FAT4 突变的 PH 患者的人类神经元祖细胞 (hNPC) 以及同基因系在移植到小鼠大脑中时，迁移动力学发生了改变。通过移植 hNPC 的电子显微镜分析、皮质类器官的蛋白质印迹分析以及巴弗洛霉素 A1 存在下的 hNPC 延时成像，在体内观察到受影响的迁移与自噬的改变有关。我们进一步表明，自噬缺陷导致桩蛋白（一种参与细胞迁移的粘着斑蛋白）的积累。引人注目的是，hNPC 的单细胞 RNA-seq 分析显示自噬相关基因的表达水平相似。FDA 批准的药物二甲双胍增强 AMPK 依赖性自噬，促进了 PH 患者来源的 hNPC 的迁移。我们的数据表明，自噬中与转录无关的稳态修饰导致 hNPC体内有缺陷的迁移行为，并表明调节 hNPC 中的自噬可能会挽救某些形式的 PH 中的神经元迁移缺陷。