title: TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD.
abstract: Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43-deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Ling
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. wong@jhmi.edu.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D053595:Embryonic Stem Cells; D005091:Exons / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics*; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics; D012326:RNA Splicing; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D000071183:Autophagy-Related Proteins; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C000598624:TARDBP protein, human; C578077:Tardbp protein, mouse; C507524:ATG4B protein, human