LAUSR

Hutchinson‐Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature aging and primarily caused by the accumulation of progerin, a mutant form of lamin A. Although the effects of progerin on multiple tissues have been previously studied, its impact on brain development is not completely understood. We established cortical organoids derived from HGPS patient‐induced pluripotent stem cells (iPSCs) from patients with HGPS to investigate the role of progerin in the brain. HGPS cortical organoids showed hallmarks of HGPS pathology, including elevated progerin expression and irregular nuclear morphology during early developmental stages. Additionally, we observed abnormal morphology and increased cellular senescence specifically in the rosette regions of HGPS organoids. This senescence appeared to interfere with normal neuronal differentiation, resulting in a significant reduction in mature neuron development and synapse formation in HGPS cortical organoids. Transcriptome profiling of HGPS cortical organoids revealed the downregulation of key genes related to neural development and synapse formation, with these changes persisting over time, potentially contributing to impaired neuronal differentiation and maturation. These findings suggest the role of progerin in early neural development and establish cortical organoids as a model for studying HGPS‐related brain development.