ERA-Net E-Rare

Amyotrophic Lateral Sclerosis (ALS) is a rare group of neurological diseases with a tremendous burden on patients and their families, as well as a significant impact on society. ALS is characterized by progressive upper and lower motor neuron (MN) loss due to both cell autonomous and non-autonomous death mechanisms that are largely unknown. Understanding these mechanisms is crucial for developing therapeutics because of the lack of effective treatment for ALS. Based on our previous data showing the role of glial toxicity on MN pathology, we hypothesize that the risk for ALS is associated with alterations in immune and energy metabolism genes/pathways. The main goal of this proposal will be to unravel the role of immune and cell metabolism in ALS pathophysiology by applying integrated multi-omics approaches in relevant ALS models based on induced pluripotent stem cell (iPSC) 2/3D models (mini-brain/spinal cord). To this end, we will: 1) generate and characterize iPSC differentiated cells (MNs and glia) from familial ALS (TDP43/C9) subjects with different clinical phenotypes as well as isogenic (corrected) controls; 2) apply omics approaches (genomic, transcriptomic, proteomic and metabolomic) in ALS-iPSC systems; 3) validate candidate genes/pathways and assess their potential therapeutic role in cell-based platforms. This project involves academic partners with solid expertise in ALS, iPSC technology and omics. This unique combined international effort will allow assessing the role of energy metabolism and immune pathways in ALS pathogenesis and as therapeutic targets.