{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:15:47Z","timestamp":1787008547590,"version":"build-2736575974"},"reference-count":77,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T00:00:00Z","timestamp":1715558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017562","name":"Temerty Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017562","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awae078","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T17:10:40Z","timestamp":1709745040000},"page":"2053-2068","source":"Crossref","is-referenced-by-count":15,"title":["Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models"],"prefix":"10.1093","volume":"147","author":[{"given":"Cristian A","family":"Droppelmann","sequence":"first","affiliation":[{"name":"Molecular 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Ontario N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Szabla","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University , London, Ontario N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor A","family":"Lyons","sequence":"additional","affiliation":[{"name":"Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University , London, Ontario N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hind","family":"Amzil","sequence":"additional","affiliation":[{"name":"Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University , London, Ontario N6A 5C1 , 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Western University , London, Ontario N6A 5B7 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Buratti","sequence":"additional","affiliation":[{"name":"International Centre for Genetic Engineering and Biotechnology (ICGEB), AREA Science Park , 34149 Trieste , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murray","family":"Junop","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University , London, Ontario N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie M","family":"Kramer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University , Halifax, Nova Scotia B3H 4R2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1988-6262","authenticated-orcid":false,"given":"Michael 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