Investigating a neurodevelopmental origin of amyotrophic lateral sclerosis – OriginALS

Although they mainly affect adults, some neurodegenerative diseases may have a neurodevelopmental origin and remain silent during childhood, adolescence and part of adulthood, thanks to compensatory mechanisms. The first symptoms of the disease would appear following the collapse of these compensatory mechanisms, for reasons that are still unknown. On the basis of recent literature demonstrating a neurodevelopmental contribution to Huntington's disease, and preliminary data obtained in two mouse models of amyotrophic lateral sclerosis (ALS), we propose to investigate the developmental origin of familial ALS. We will study the motor cortex and lumbar spinal cord, and employ a multidisciplinary approach including pharmacological, cellular (electrophysiology, imaging) and molecular (omics) analyses to be conducted at perinatal stages. Our study will be carried out on mouse models of ALS, chosen for their reliability and their genetic and symptomatic complementarity. Results will be validated on ALS patient-derived organoids and their isogenic controls. The aim of this project is to enrich our understanding of the temporal origin of ALS and associated mechanisms, in order to propose new therapeutic approaches.