title: Studies of alternative isoforms provide insight into TDP-43 autoregulation and pathogenesis.
abstract: TDP-43 is a soluble, nuclear protein that undergoes cytoplasmic redistribution and aggregation in the majority of cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 autoregulates the abundance of its own transcript TARDBP by binding to an intron in the 3' untranslated region, although the mechanisms underlying this activity have been debated. Herein, we provide the most extensive analysis of TARDBP transcript yet undertaken. We detail the existence of a plethora of complex splicing events and alternative poly(A) use and provide data that explain the discrepancies reported to date regarding the autoregulatory capacity of TDP-43. Additionally, although many splice isoforms emanating from the TARDBP locus contain the regulated intron in the 3' UTR, we find only evidence for autoregulation of the transcript encoding full-length TDP-43. Finally, we use a novel cytoplasmic isoform of TDP to induce disease-like loss of soluble, nuclear TDP-43, which results in aberrant splicing and up-regulation of endogenous TARDBP. These results reveal a previously underappreciated complexity to TDP-43 regulated splicing and suggest that loss of TDP-43 autoregulatory capacity may contribute to the pathogenesis of ALS.
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida 32610, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: D'Alton
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida 32610, USA.
authors.forename: Marcelle
authors.initials: M
authors.lastname: Altshuler
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida 32610, USA.
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
mesh_terms: D020413:3' Untranslated Regions; D017398:Alternative Splicing; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D057174:Frontotemporal Lobar Degeneration / Q000209:etiology* / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007438:Introns; D051379:Mice; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C000598624:TARDBP protein, human; C578077:Tardbp protein, mouse
keywords: ALS; FTLD; TDP-43; autoregulation; splicing