Human SPG11 cerebral organoids reveal cortical neurogenesis impairment

• Published in: Human molecular genetics Vol. 28; no. 6; pp. 961 - 971
• Main Authors: Pérez-Brangulí, Francesc, Buchsbaum, Isabel Y, Pozner, Tatyana, Regensburger, Martin, Fan, Wenqiang, Schray, Annika, Börstler, Tom, Mishra, Himanshu, Gräf, Daniela, Kohl, Zacharias, Winkler, Jürgen, Berninger, Benedikt, Cappello, Silvia, Winner, Beate
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15.03.2019
• Subjects: Alleles; beta Catenin; Biomarkers; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; Cerebral Cortex - physiopathology; Cognition Disorders - genetics; Cognition Disorders - physiopathology; Disease Susceptibility; Fluorescent Antibody Technique; Genotype; Glycogen Synthase Kinase 3 - metabolism; Humans; Mutation; Neurogenesis - genetics; Organoids; Phenotype; Proteins - genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddy397

Abstract 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.