01695nas a2200181   4500000000100000000000100001008004100002260000900043100002500052700002700077700002500104245010600129856006200235300001100297490000800308520118300316022001401499       2026                            d  c20261 aKristel N. Eigenhuis1 aRoberto Montoro Ferrer1 aR. Jeroen Pasterkamp00aNeural Organoid Models as a Platform for Studying Disease Mechanisms in Amyotrophic Lateral Sclerosis  uhttps://onlinelibrary.wiley.com/doi/abs/10.1111/jnc.70513  ae705130 v1703 aAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons leading to muscle wasting. However, structural and molecular abnormalities, including cortical thinning and TDP-43 pathology, extend into frontal, parietal, and temporal areas, pointing to defects across broader cortical regions. The advent of human induced pluripotent stem cell (hiPSC) technology has enabled the generation of human-specific brain cell types in vitro. Here, we provide an overview of the three-dimensional (3D) hiPSC-derived neural organoid platforms used to model cortical structures and to study cortical ALS-associated phenotypes. We review which pathological hallmarks have been recapitulated in these organoids and discuss disease phenotypes reported to date. Further, we comprehensively cover different neural organoid models and experimental strategies, including patient-derived hiPSC models and exogenous pathology induction, while addressing current technical challenges. Together, these advances position neural organoids as an emerging tool to study cell-type-specific and circuit-level mechanisms related to cortical changes in ALS.  a1471-4159