Our main goal is to investigate the pathomechanisms characterizing the motoneurons of amyotrophic lateral sclerosis (ALS) patients by using in vitro models based on human induced pluripotent stem cells (hiPSC). Thanks to the state-of-the-art setup for hiPSC cultures present at the Insitute of Anatomy and Cell Biology and in direct collaboration with the Ulm site of the DZNE, we combine 2D neuronal cultures, cerebral and spinal organoids with multi-omics approaches to uncover the pathologic alterations that drive neurodegeneration and depict a common “pathogenic signature” shared by different cases of ALS. In particular, we focus on synaptic aberrations and catabolic dysfunctions with the final goal of identifying novel therapeutic targets for the treatment of ALS.