2. Academic Validation
  3. SON-dependent nuclear speckle rehabilitation alleviates proteinopathies

SON-dependent nuclear speckle rehabilitation alleviates proteinopathies

  • bioRxiv. 2025 Apr 28:2024.04.18.590103. doi: 10.1101/2024.04.18.590103.
William Dion 1,  Yuren Tao 2,  Maci Chambers 1,  Shanshan Zhao 2,  Riley K Arbuckle 3 4,  Michelle Sun 1,  Syeda Kubra 1,  Matthew A Schaich 5 6,  Yuhang Nie 2,  Megan Ye 1,  Imran Jamal 1,  Mads B Larsen 1,  Daniel Camarco 1,  Eleanor Ickes 1,  Haokun H Wang 1,  C DuPont 1,  Bingjie Wang 3,  Silvia Liu 6 7 8,  Shaohua Pi 3,  Bennet Van Houten 5 6,  Bill B Chen 1 9,  Yuanyuan Chen 3 6,  Xu Chen 2,  Bokai Zhu 1 7 10
Affiliations

Affiliations

  • 1 Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
  • 2 Department of Neuroscience, School of Medicine, University of California, San Diego, CA, U.S.A.
  • 3 Department of Ophthalmology, University of Pittsburgh School of Medicine, PA, U.S.A.
  • 4 Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
  • 5 UPMC Hillman Cancer Center, University of Pittsburgh, PA, U.S.A.
  • 6 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA, U.S.A.
  • 7 Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, U.S.A.
  • 8 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
  • 9 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
  • 10 Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
PMID: 38659924 DOI: 10.1101/2024.04.18.590103
Abstract

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 identified 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 protected 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 were observed in human tauopathies. Our study provides proof-of-principle of targeting nuclear speckles to ameliorate proteinopathies.

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