室管腔周围神经元异位症（PH）是人类皮层中最常见的皮质畸形之一。我们表明，来自携带DCHS1或FAT4突变的PH患者及等位基因株的人类神经元祖细胞（hNPCs），在移植到小鼠脑内时，其迁移动力学发生了改变。受影响的迁移与体内移植hNPCs的电子显微镜分析、皮质器官样体的Western blot分析以及存在bafilomycin A1时hNPCs的时间成像的异常自噬相关。我们进一步表明，自噬缺陷导致paxillin的积累，paxillin是参与细胞迁移的一个黏附斑蛋白。引人注目的是，hNPCs的单细胞RNA-seq分析显示了类似的自噬相关基因表达水平。通过二甲双胍，一种FDA批准的药物，增强AMPK依赖的自噬过程，促进了PH患者源hNPCs的迁移。我们的数据表明，在体内，非转录的自噬调节变化对hNPCs的缺陷迁移行为做出了贡献，而调控hNPCs的自噬可能会挽救一些PH形式中的神经元迁移缺陷。© 2023 The Authors. 根据CC BY 4.0许可发布。

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.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.