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大学・研究所にある論文を検索できる 「Pathogenic mutation of TDP-43 impairs RNA processing in a cell type-specific manner : implications for the pathogenesis of ALS/FTLD (本文)」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
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Pathogenic mutation of TDP-43 impairs RNA processing in a cell type-specific manner : implications for the pathogenesis of ALS/FTLD (本文)

今泉, 研人 慶應義塾大学

2022.08.29

概要

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 degener- ation (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 impair- ments 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.

Key words: amyotrophic lateral sclerosis; frontotemporal lobar degeneration; induced pluripotent stem cell; TDP-43

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