TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis

Brain. 2018 May 1;141(5):1320-1333. doi: 10.1093/brain/awy062.


See Fratta and Isaacs (doi:10.1093/brain/awy091) for a scientific commentary on this article.The RNA binding proteins TDP-43 (encoded by TARDBP) and hnRNP A1 (HNRNPA1) are each mutated in certain amyotrophic lateral sclerosis cases and are often mislocalized in cytoplasmic aggregates within motor neurons of affected patients. Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of frontotemporal dementia cases. Here, we report that TDP-43 binds HNRNPA1 pre-mRNA and modulates its splicing, and that depletion of nuclear TDP-43 results in increased inclusion of a cassette exon in the HNRNPA1 transcript, and consequently elevated protein levels of an isoform containing an elongated prion-like domain, referred to as hnRNP A1B. Combined in vivo and in vitro approaches demonstrated greater fibrillization propensity for hnRNP A1B, which drives protein aggregation and is toxic to cells. Moreover, amyotrophic lateral sclerosis patients with documented TDP-43 pathology showed neuronal hnRNP A1B cytoplasmic accumulation, indicating that TDP-43 mislocalization may contribute to neuronal vulnerability and loss via altered HNRNPA1 pre-mRNA splicing and function. Given that TDP-43 and hnRNP A1 each bind, and thus modulate, a third of the transcriptome, our data suggest a much broader disruption in RNA metabolism than previously considered.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / drug effects
  • Alternative Splicing / genetics*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dactinomycin / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • HEK293 Cells
  • HeLa Cells
  • Heterogeneous Nuclear Ribonucleoprotein A1 / genetics*
  • Heterogeneous Nuclear Ribonucleoprotein A1 / metabolism
  • Humans
  • Immunoprecipitation
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Mutation / genetics
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Oligopeptides / genetics
  • Oligopeptides / metabolism
  • Protein Aggregation, Pathological / metabolism*
  • RNA Splice Sites / drug effects
  • RNA Splice Sites / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Spinal Cord / pathology
  • Transfection


  • DNA-Binding Proteins
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Nucleic Acid Synthesis Inhibitors
  • Oligopeptides
  • RNA Splice Sites
  • RNA, Messenger
  • RNA, Small Interfering
  • TARDBP protein, human
  • Dactinomycin

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