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<p>TDP-43, a multifaceted RNA-binding protein (RBP), has emerged as a key regulator in neurodegenerative diseases. Yet, its underlying mechanisms of action across other diseases remain unclear. This review covers TDP-43’s structural domains, its pathology in neurodegenerative diseases, and its liquid-liquid phase separation (LLPS) properties, where the disease pathology and LLPS together drive its aggregate-forming behavior. This review then focuses on the nucleocytoplasmic shuttling mechanisms of TDP-43, analyzing their role in governing its subcellular localization and functional diversity. The review further summarizes how TDP-43 modulates cellular metabolism (encompassing lipid, glucose, and ATP homeostasis) and cell death pathways in neurological disorders, cancer, and immunity. Finally, this review highlights unresolved questions, including the putative role of TDP-43 as an RBP in post-transcriptional RNA modification and the regulatory networks controlling its expression, thereby providing directions for clinical diagnosis and treatment of TDP-43-associated diseases.</p>

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TDP-43: unveiling the hidden key to cellular fate decisions

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月22日

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  • Bowen Liu,
  • Xin Chen,
  • Jin Wang,
  • Jingjing Chen,
  • Bingqian Zhao,
  • Xin Jin,
  • Mingjun Jiang,
  • Jingru Wang,
  • Wei Liao,
  • Bo Yang,
  • Xiaofang Geng

摘要

TDP-43, a multifaceted RNA-binding protein (RBP), has emerged as a key regulator in neurodegenerative diseases. Yet, its underlying mechanisms of action across other diseases remain unclear. This review covers TDP-43’s structural domains, its pathology in neurodegenerative diseases, and its liquid-liquid phase separation (LLPS) properties, where the disease pathology and LLPS together drive its aggregate-forming behavior. This review then focuses on the nucleocytoplasmic shuttling mechanisms of TDP-43, analyzing their role in governing its subcellular localization and functional diversity. The review further summarizes how TDP-43 modulates cellular metabolism (encompassing lipid, glucose, and ATP homeostasis) and cell death pathways in neurological disorders, cancer, and immunity. Finally, this review highlights unresolved questions, including the putative role of TDP-43 as an RBP in post-transcriptional RNA modification and the regulatory networks controlling its expression, thereby providing directions for clinical diagnosis and treatment of TDP-43-associated diseases.