title: Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.
abstract: We used cross-linking and immunoprecipitation coupled with high-throughput sequencing to identify binding sites in 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein that, when mutated, causes amyotrophic lateral sclerosis. Massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs were changed (including Fus (Tls), progranulin and other transcripts encoding neurodegenerative disease-associated proteins) and 965 altered splicing events were detected (including in sortilin, the receptor for progranulin) following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides. RNAs whose levels were most depleted by reduction in TDP-43 were derived from genes with very long introns and that encode proteins involved in synaptic activity. Lastly, we found that TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation.
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California, USA.
authors.forename: Magdalini
authors.initials: M
authors.lastname: Polymenidou
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.forename: Kasey R
authors.initials: KR
authors.lastname: Hutt
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Huelga
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Moran
authors.forename: Tiffany Y
authors.initials: TY
authors.lastname: Liang
authors.forename: Shuo-Chien
authors.initials: SC
authors.lastname: Ling
authors.forename: Eveline
authors.initials: E
authors.lastname: Sun
authors.forename: Edward
authors.initials: E
authors.lastname: Wancewicz
authors.forename: Curt
authors.initials: C
authors.lastname: Mazur
authors.forename: Holly
authors.initials: H
authors.lastname: Kordasiewicz
authors.forename: Yalda
authors.initials: Y
authors.lastname: Sedaghat
authors.forename: John Paul
authors.initials: JP
authors.lastname: Donohue
authors.forename: Lily
authors.initials: L
authors.lastname: Shiue
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D005260:Female; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D012322:RNA Precursors / Q000037:antagonists & inhibitors / Q000235:genetics*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; D012322:RNA Precursors; D012333:RNA, Messenger