Qki5 safeguards spinal motor neuron function by defining the motor neuron- specific transcriptome via pre- mRNA

• 成果类型: Article
• 署名作者: Hayakawa-Yano, Yoshika; Furukawa, Takako; Matsuo, Tsuyoshi; Ogasawara, Takahisa; Nogami, Masahiro; Yokoyama, Kazumasa; Yugami, Masato; Shinozaki, Munehisa; Nakamoto, Chihiro; Sakimura, Kenji; Koyama, Akihide; Ogi, Kazuhiro; Onodera, Osamu; Takebayashi, Hirohide; Okano, Hideyuki; Yano, Masato
• 署名单位: Niigata University; Keio University; Keio University; Takeda Pharmaceutical Company Ltd; Niigata University; Niigata University; Niigata University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11126
• DOI: 10.1073/pnas.2401531121
• 发表日期: 2024-09-10
• 关键词: frontotemporal lobar degeneration; binding proteins; stem-cells; expression; quaking; subtype; disease; tdp-43; agrin; fus

摘要

Many RNA- binding proteins (RBPs) are linked to the dysregulation of RNA metabolism in motor neuron diseases (MNDs). However, the molecular mechanisms underlying MN vulnerability have yet to be elucidated. Here, we found that such an RBP, Quaking5 (Qki5), contributes to formation of the MN- specific transcriptome profile, termed MN- ness, through the posttranscriptional network and maintenance of the mature MNs. Immunohistochemical analysis and single- cell RNA sequencing (scRNA- seq) revealed that Qki5 is predominantly expressed in MNs, but not in other neuronal popanalyses revealed that Qki5- dependent RNA regulation plays a pivotal role in generating the MN- specific transcriptome through pre- messenger ribonucleic acid (mRNA) splicing for the synapse- related molecules and c- Jun N- terminal kinase/stress- activated protein caused neurodegeneration in postnatal mice and loss of Qki5 function resulted in the aberrant activation of stress- responsive JNK/SAPK pathway both in vitro and in vivo. These data suggested that Qki5 plays a crucial biological role in RNA regulation and safeguarding of MNs and might be associated with pathogenesis of MNDs.