Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are considered part of a common and heterogeneous clinical, genetic, and neuropathological spectrum. Despite years of research and advances in understanding, the underlying pathogenic mechanisms of these diseases remain unknown. In this project, our group redefines the understanding of both pathologies based on previously obtained and published results. Based on these findings, we hypothesize that the ALS-FTD spectrum forms a continuous pathological process, where the clinical entities that begin in one form gradually transition and include alterations of the opposite clinical form. In other words, ALS transitions to ALS-FTD, and vice versa, FTD transitions to FTD-ALS; this progression is conditioned by the genetic, molecular, immunological, and environmental factors of each patient. This explains the existence of all the clinical heterogeneous and diverse forms of both diseases within the ALS-FTD spectrum.

Given this, we believe that the molecular alterations observed in regions that are secondarily affected in one clinical form but correspond to regions that are primarily affected in the opposite clinical form, could correspond to very early alterations that occur in the opposite clinical form. This is because these regions are primarily affected in the opposite clinical form, where we can never observe the initial molecular alterations, as we always observe the later ones due to the advanced stage of the pathology. 

Based on this axiom, we aim to transcriptionally characterize these secondarily affected regions in human post-mortem samples and compare this transcriptomic profile with that of organoids composed of neurons located in regions with primary involvement and carrying a TARDBP gene mutation that causes ALS and FTD at early stages, to simulate an initial phase of involvement. Once we have both transcriptomic profiles, we will study the common and specific pathways in each of the models used. Through computational biology, we will create in silico models to identify potential drugs to reverse these alterations. Subsequently, we will test these candidates in complete in vitro models of neurons co-cultured with glial cells, all derived from iPSCs with a TARDBP mutation, in order to validate new therapeutic candidates for the very early stages of the disease and attempt to clarify the possible molecular causes of these diseases.