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

Autor:	Droppelmann CA; Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada., Campos-Melo D; Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada., Noches V; Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada., McLellan C; Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada., Szabla R; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada., Lyons TA; Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada., Amzil H; Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada., Withers B; Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada., Kaplanis B; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada., Sonkar KS; International Centre for Genetic Engineering and Biotechnology (ICGEB), AREA Science Park, 34149 Trieste, Italy., Simon A; Department of Biology, Faculty of Science, Western University, London, Ontario N6A 5B7, Canada., Buratti E; International Centre for Genetic Engineering and Biotechnology (ICGEB), AREA Science Park, 34149 Trieste, Italy., Junop M; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada., Kramer JM; Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada., Strong MJ; Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada.; Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, Canada.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Jun 03; Vol. 147 (6), pp. 2053-2068.
DOI:	10.1093/brain/awae078
Abstrakt:	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. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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