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- Title
Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models.
- Authors
Droppelmann, Cristian A; Campos-Melo, Danae; Noches, Veronica; McLellan, Crystal; Szabla, Robert; Lyons, Taylor A; Amzil, Hind; Withers, Benjamin; Kaplanis, Brianna; Sonkar, Kirti S; Simon, Anne; Buratti, Emanuele; Junop, Murray; Kramer, Jamie M; Strong, Michael J
- 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.
- Subjects
AMYOTROPHIC lateral sclerosis; DNA-binding proteins; GUANINE nucleotide exchange factors; PHENOTYPES; TDP-43 proteinopathies; RILUZOLE; TAU proteins
- Publication
Brain: A Journal of Neurology, 2024, Vol 147, Issue 6, p2053
- ISSN
0006-8950
- Publication type
Article
- DOI
10.1093/brain/awae078