TY - JOUR T1 - Pathogenic Mutation of TDP-43 Impairs RNA Processing in a Cell Type-Specific Manner: Implications for the Pathogenesis of ALS/FTLD JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0061-22.2022 VL - 9 IS - 3 SP - ENEURO.0061-22.2022 AU - Kent Imaizumi AU - Hirosato Ideno AU - Tsukika Sato AU - Satoru Morimoto AU - Hideyuki Okano Y1 - 2022/05/01 UR - http://www.eneuro.org/content/9/3/ENEURO.0061-22.2022.abstract N2 - 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 processing. 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 expression, 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 unprecedented cell type specificity of TDP-43 LOF in ALS/FTLD pathogenesis. ER -