Brain Organoids Reveal Disease Mechanisms in Rare Genetic Disorder Lissencephaly
Mannheim,Germany - February 13,2025 – Researchers at the Central Institute for Mental Health (ZI) and the Hector Institute for Translational Brain Research (HITBR) have utilized patient-derived brain organoids to uncover key molecular disruptions in LIS1-lissencephaly,a rare and severe neurodevelopmental disorder. The findings, published today in Nature Communications, offer new avenues for understanding disease progression and developing personalized therapies.
Lissencephaly, meaning “smooth brain,” is characterized by a lack of normal brain folds and frequently enough results in critically important developmental delays, intellectual disability, and seizures. It’s frequently caused by mutations in the LIS1 gene, but the precise mechanisms by which these mutations lead to brain malformation have remained elusive. This new research provides a crucial step toward unraveling those complexities.
The study focused on forebrain organoids - three-dimensional, miniature versions of the brain grown from patient-derived induced pluripotent stem cells.By analyzing these organoids, the team identified widespread proteostasis dysregulation, meaning problems with protein folding, stability, and clearance, as a central feature of the disease. this disruption impacts numerous cellular processes critical for healthy brain development.
“Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids,” explained Dr.Julia Ladewig of the HITBR and ZI, the study’s lead contact. “These organoids allow us to model the disease in a way that wasn’t previously possible, providing a platform to investigate the underlying causes and test potential treatments.”
The ZI is a leading institution in psychiatric research and a location of the German Center for Mental Health (dzpg.org), institutionally linked to the University of Heidelberg. The HITBR was founded as a joint project of the ZI, the German Cancer Research Center (DKFZ), and the Hector Foundation II, aiming to identify new therapeutic targets for severe psychiatric illnesses and brain tumors.
The research is available online at: https://www.nature.com/articles/s41467-025-64980-0
