Ricerc@Sapienza

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neurons (MNs) death in the spinal cord and brain, leading the loss of skeletal muscle mass (muscle atrophy). So far it has been difficult to investigate the molecular pathways of ALS because of the lack of suitable cell model system. The use of induced pluripotent stem cells (iPSC) carrying ALS mutations introduced by gene editing, represents a valuable opportunity for the study of this pathology. At the state-of-art, important improvements have been done concerning molecular processes which are involved in ALS pathology. Mutations in FUS protein have been reported in different ALS-patients. Despite its nuclear localization, FUS can shuttle between the nucleus and the cytoplasm under specific conditions. It has been reported that a hallmark of ALS disease is the abnormal cytoplasmatic accumulation of the mutated protein and NMJ degeneration has been observed as an early pathogenic event in ALS pathology. In addition, preliminary data collected in my lab highlight an aberrant increase in axon branching and growth in FUS-mutated MNs. The principal aim of my PhD project is to confirm whether the aberrant axon phenotypes observed might be involved in the neuromuscular disruption. To recapitulate the NMJ circuit formation in vitro I will take advantage from using iPSCs to obtain neural-muscle systems by 2D co-cultures and 3D organoids. The study of NMJ impairment will be conducted thanks to morphological and functional assays to verify the FUS mutation involvement in the ALS progression. Finally, the discovery of these cellular processes represents a crucial step in order to contribute to the development of more personalized future therapies.