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.

Centro de Investigaciones Biológicas Margarita Salas C S 1 C Madrid Spain

Department of Cell Biology and Physiology University of North Carolina Chapel Hill North Carolina USA

Department of Cellular Neurophysiology Institute of Experimental Medicine CAS Prague Czech Republic

Department of Neurodegenerative Diseases Beckman Research Institute of City of Hope Duarte California USA

Department of Translational Neuroscience UMC Utrecht Brain Center University Medical Center Utrecht Utrecht University Utrecht the Netherlands

Faculty of Science Charles University Prague Czech Republic

Laboratory of Astrocyte Biology and CNS Regeneration Center of Brain Repair Department of Clinical Neuroscience Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Gotenburg Sweden

Laboratory of Gene Expression Institute of Biotechnology of the Czech Academy of Sciences Vestec Czech Republic

Laboratory of Glial Biology and Omics Technologies Institute of Biotechnology of the Czech Academy of Sciences Vestec Czech Republic

Stem Cells Aging and Neurodegeneration Lund Stem Cell Center Department of Experimental Medical Science Faculty of Medicine Lund University Lund Sweden

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