Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models

Brain. 2024 Jun 3;147(6):2053-2068. doi: 10.1093/brain/awae078.

Abstract

Aggregation of the RNA-binding protein TAR DNA binding protein (TDP-43) is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As 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 RNA-binding protein rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that an N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs of TDP-43 competing with RNA and that the IPT/TIG domain of NF242 is essential for this interaction. Genetic 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 a strong affinity for TDP-43 aggregates and a mechanism that includes competition with RNA sequestration, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD.

Keywords: RNA binding proteins; RNA metabolism; amyotrophic lateral sclerosis; motor neuron disease; neuronal cytoplasmic inclusions; therapeutic.

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Amyotrophic Lateral Sclerosis* / pathology
  • Animals
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Disease Models, Animal*
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Guanine Nucleotide Exchange Factors* / genetics
  • Guanine Nucleotide Exchange Factors* / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Phenotype*

Substances

  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • TARDBP protein, human
  • Tardbp protein, mouse
  • Drosophila Proteins