Mitigation of TDP-43-induced toxic phenotype by expression of RGNEF N-terminal fragment in ALS models

Aggregation of the RNA-binding protein (RBP) TDP-43 is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Since TDP-43 aggregation and dysregulation are causative of neuronal death, there is a special interest in targeting this protein as a therapeutic approach. Previously, we found that TDP-43 extensively co-aggregated with the dual function protein (GEF (guanine exchange factor) and RBP) rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that a N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs (RRM) of TDP-43 competing with RNA, and that the IPT/TIG domain of NF242 is essential for this interaction. Genetical expression of NF242 in a fruit fly ALS model overexpressing TDP-43 suppressed the neuropathological phenotype increasing lifespan, abolishing motor defects, and preventing neurodegeneration. Intracerebroventricular injections of AAV9/NF242 in a severe TDP-43 murine model (rNLS8) improved lifespan and motor phenotype, and decreased neuroinflammation markers. Our results demonstrate an innovative way to target TDP-43 proteinopathies using a protein fragment with affinity for TDP-43, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD.