TARTROPISM

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons (MNs). Ten percent of ALS cases are of genetic origin, involving mutations in genes linked to key cellular processes. TDP-43 protein is found aggregated as pathological inclusions in over 97% of ALS cases. Around fifty pathogenic variants responsible for ALS have been identified in the TARDBP gene, which encodes TDP-43, with most mutations located in the protein’s prion-like domain. We recently identified a new variant in this domain (glycine substitution in valine at position 376; TDP-43-G376V) that is associated with distal myopathy rather than ALS. This variant does not present increased morbidity and does not meet the typical criteria for ALS. Our objective is to understand why and how this variant does not affect MNs but exhibits a pathological tropism for muscle tissue, whereas two other variants affecting the same amino acid residu (TDP-43-G376D and G376A) are ALS-causing. We will investigate the molecular mechanisms that confer resistance to MNs involvement in the G376V variant and search for modifying factors capable of suppressing the pathogenicity of this variant in MNs. Induced pluripotent stem cells (iPSCs) derived from patients and transgenic Drosophila models will be used to assess the functional impact of G376V, G376D, and G376A variants in both MNs and muscle cells. Additionally, whole-genome sequencing of patients carrying these variants will be performed to identify suppressors that cause the G376V variant to exhibit muscle-specific pathology. Once identified, the impact of suppressor(s) will be measured in MNs derived from engineered G376D and G376A iPSCs or transgenic Drosophila models. Characterizing the impact of these variants will allow us to (1) understand the pleiotropic effects of TARDBP variants and (2) identify new therapeutic targets to fight this devastating disease.