Pathogenic Mutation of TDP-43 Impairs RNA Processing in a Cell Type-Specific Manner: Implications for the Pathogenesis of ALS/FTLD

Kent Imaizumi, Hirosato Ideno, Tsukika Sato, Satoru Morimoto, Hideyuki Okano

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Transactivating response element DNA-binding protein of 43 kDa (TDP-43), which is encoded by the TARDBP gene, is an RNA-binding protein with fundamental RNA processing activities, and its loss-of-function (LOF) has a central role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TARDBP mutations are postulated to inactivate TDP-43 functions, leading to impaired RNA proc-essing. However, it has not been fully examined how mutant TDP-43 affects global RNA regulation, especially in human cell models. Here, we examined global RNA processing in forebrain cortical neurons derived from human induced pluripotent stem cells (iPSCs) with a pathogenic TARDBP mutation encoding the TDP-43K263E protein. In neurons expressing mutant TDP-43, we detected disrupted RNA regulation, including global changes in gene ex-pression, missplicing, and aberrant polyadenylation, all of which were highly similar to those induced by TDP-43 knock-down. This mutation-induced TDP-43 LOF was not because of the cytoplasmic mislocalization of TDP-43. Intriguingly, in nonneuronal cells, including iPSCs and neural progenitor cells (NPCs), we did not observe impairments in RNA processing, thus indicating that the K263E mutation results in neuron-specific LOF of TDP-43. This study characterizes global RNA processing impairments induced by mutant TDP-43 and reveals the unprece-dented cell type specificity of TDP-43 LOF in ALS/FTLD pathogenesis.

Original languageEnglish
Article numberENEURO.0061-22.2022
Issue number3
Publication statusPublished - 2022 May 1


  • TDP-43
  • amyotrophic lateral sclerosis
  • frontotemporal lobar degeneration
  • induced pluripotent stem cell

ASJC Scopus subject areas

  • Neuroscience(all)


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