{"doi":"10.1093/brain/awae078","title":"Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models","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.","journal":"Brain","year":2024,"id":431588,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9609,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1192714,"name":"Danae Campos‐Melo","orcid":"0009-0006-2681-7790","position":1,"is_corresponding":false},{"id":892541,"name":"Verónica Noches","orcid":null,"position":2,"is_corresponding":false},{"id":1193113,"name":"Crystal McLellan","orcid":null,"position":3,"is_corresponding":false},{"id":1192715,"name":"Robert Szabla","orcid":"0000-0002-6379-232X","position":4,"is_corresponding":false},{"id":1193114,"name":"Taylor A. Lyons","orcid":null,"position":5,"is_corresponding":false},{"id":1193115,"name":"Hind Amzil","orcid":null,"position":6,"is_corresponding":false},{"id":1193116,"name":"Benjamin Withers","orcid":null,"position":7,"is_corresponding":false},{"id":1236306,"name":"Brianna Kaplanis","orcid":null,"position":8,"is_corresponding":false},{"id":814413,"name":"Kirti Shila Sonkar","orcid":"0000-0002-8382-1140","position":9,"is_corresponding":false},{"id":1075790,"name":"Anne F. Simon","orcid":"0000-0002-6509-4541","position":10,"is_corresponding":false},{"id":678025,"name":"Emanuele Buratti","orcid":"0000-0002-1356-9074","position":11,"is_corresponding":false},{"id":975781,"name":"M.S. Junop","orcid":"0000-0001-6676-5717","position":12,"is_corresponding":false},{"id":1192716,"name":"Jamie M. Kramer","orcid":"0000-0002-0924-1279","position":13,"is_corresponding":false},{"id":1028025,"name":"Michael J. Strong","orcid":"0000-0003-1988-6262","position":14,"is_corresponding":false},{"id":1192713,"name":"Cristian A. Droppelmann","orcid":"0000-0002-0474-6112","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T01:59:30.747263Z","pmid":"38739752","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}