Dykstra Werner, Matusova Zuzana, Battaglia Rachel A, Abaffy Pavel, Goya-Iglesias Nuria, Pérez-Sala Dolores, Ahlenius Henrik, Kubista Mikael, Pasterkamp R Jeroen, Li Li, Chao Jianfei, Shi Yanhong, Valihrach Lukas, Pekny Milos, Hol Elly M
Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Laboratory of Glial Biology and Omics Technologies, Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic.
Glia. 2025 Nov;73(11):2167-2188. doi: 10.1002/glia.70049. Epub 2025 Jul 30.
Glial fibrillary acidic protein (GFAP) is a type-3 intermediate filament protein mainly expressed in astrocytes in the central nervous system. Mutations in GFAP cause Alexander disease (AxD), a rare and fatal neurological disorder. How exactly mutant GFAP eventually leads to white and gray matter deterioration in AxD remains unknown. GFAP is known to be expressed also in neural precursor cells in the developing brain. Here, we used AxD patient-derived induced pluripotent stem cells (iPSCs) to explore the impact of mutant GFAP during neurodifferentiation. Our results show that GFAP is already expressed in iPSCs. Moreover, we have found that mutations in GFAP can severely affect neural organoid development through altering lineage commitment in embryoid bodies. Together, these results support the notion that GFAP plays a role as an early modulator of neurodevelopment.
胶质纤维酸性蛋白（GFAP）是一种3型中间丝蛋白，主要在中枢神经系统的星形胶质细胞中表达。GFAP突变会导致亚历山大病（AxD），这是一种罕见的致命性神经疾病。突变的GFAP究竟如何最终导致AxD中的白质和灰质退化仍不清楚。已知GFAP在发育中的大脑神经前体细胞中也有表达。在这里，我们使用源自AxD患者的诱导多能干细胞（iPSC）来探究突变的GFAP在神经分化过程中的影响。我们的结果表明，GFAP在iPSC中已经表达。此外，我们发现GFAP突变可通过改变胚状体中的谱系定向来严重影响神经器官的发育。这些结果共同支持了GFAP作为神经发育早期调节因子发挥作用的观点。
