2. Academic Validation
  3. YAP maintains the dynamics of TDP-43 condensates and antagonizes TDP-43 pathological aggregates

YAP maintains the dynamics of TDP-43 condensates and antagonizes TDP-43 pathological aggregates

  • Nat Cell Biol. 2025 Jul;27(7):1148-1160. doi: 10.1038/s41556-025-01685-y.
Jiaqi Zhang # 1,  Jiaojiao Hu # 2 3,  Ruogu Liu # 1,  Tian Zhou 4,  Xuewei Luo 5,  Peigang Liang 1,  Zaichao Xie 1,  Qinyue Zhao 6 7,  Yan Chen 8,  Dan Du 5,  Cong Liu 2 3 9,  Yiming Zheng 10 11,  Dan Li 12 13,  Bo Wang 14
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 4 Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • 5 State Key Laboratory of Cellular Stress Biology, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 6 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
  • 7 Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China.
  • 8 Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, China.
  • 9 Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai, China.
  • 10 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. ymzheng@xmu.edu.cn.
  • 11 Shenzhen Research Institute of Xiamen University, Shenzhen, China. ymzheng@xmu.edu.cn.
  • 12 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China. lidan2017@sjtu.edu.cn.
  • 13 Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China. lidan2017@sjtu.edu.cn.
  • 14 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. Bowang@xmu.edu.cn.
  • # Contributed equally.
PMID: 40542195 DOI: 10.1038/s41556-025-01685-y
Abstract

Recent studies exploring the underlying pathomechanisms of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, have focused on biomolecular condensates. Here we reveal an unexpected function for YAP, a central component of the Hippo pathway, in regulating the dynamic behaviour of stress granules and TDP-43 condensates, a role that is independent of its transcriptional activity in the Hippo pathway. YAP directly binds to TDP-43. This interaction directly promotes the homotypic multimerization and phase separation of TDP-43 while inhibiting its hyperphosphorylation and solidification under stress conditions. Remarkably, YAP, whose messenger RNA levels are reduced in patients with ALS, is found to co-localize with pathological hyperphosphorylated TDP-43 aggregates in the brains of patients with ALS. In addition, elevation of YAP/Yorkie (a fly homologue of mammalian YAP) expression substantially reduces TDP-43 toxicity in primary neuron and transgenic fly models of ALS. Our findings highlight an unexpected role of YAP in managing ALS-associated biomolecular condensates, presenting important implications for potential ALS treatments.

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