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<p>Current treatments targeting individual protein quality control pathways have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common druggable target capable of global proteostasis modulation. Building upon our prior research establishing nuclear speckles as pivotal membrane-less organelles for transcriptional control of proteostasis, we aim to alleviate proteinopathies through nuclear speckle rehabilitation. We identify pyrvinium pamoate as a nuclear speckle rehabilitator that enhances protein quality control gene expression and suppresses YAP1 transcriptional activity via decreasing the surface/interfacial tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, nanomolar pyrvinium pamoate protects against retinal degeneration and tauopathy mainly by promoting autophagy and ubiquitin-proteasome activity in a SON-dependent manner without causing stress. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity are observed in human tauopathies. Our study provides proof-of-principle of targeting nuclear speckles to ameliorate proteinopathies.</p>

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SON-dependent nuclear speckle rehabilitation alleviates proteinopathies

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月5日

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  • William Dion,
  • Yuren Tao,
  • Maci Chambers,
  • Shanshan Zhao,
  • Riley K. Arbuckle,
  • Michelle Sun,
  • Syeda Kubra,
  • Matthew A. Schaich,
  • Yuhang Nie,
  • Megan Ye,
  • Imran Jamal,
  • Mads B. Larsen,
  • Daniel Camarco,
  • Eleanor Ickes,
  • Haokun H. Wang,
  • C. DuPont,
  • Bingjie Wang,
  • Silvia Liu,
  • Shaohua Pi,
  • Bennett Van Houten,
  • Bill B. Chen,
  • Yuanyuan Chen,
  • Xu Chen,
  • Bokai Zhu

摘要

Current treatments targeting individual protein quality control pathways have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common druggable target capable of global proteostasis modulation. Building upon our prior research establishing nuclear speckles as pivotal membrane-less organelles for transcriptional control of proteostasis, we aim to alleviate proteinopathies through nuclear speckle rehabilitation. We identify pyrvinium pamoate as a nuclear speckle rehabilitator that enhances protein quality control gene expression and suppresses YAP1 transcriptional activity via decreasing the surface/interfacial tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, nanomolar pyrvinium pamoate protects against retinal degeneration and tauopathy mainly by promoting autophagy and ubiquitin-proteasome activity in a SON-dependent manner without causing stress. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity are observed in human tauopathies. Our study provides proof-of-principle of targeting nuclear speckles to ameliorate proteinopathies.