SON-dependent nuclear speckle rehabilitation alleviates proteinopathies

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 Houten, Bill B. Chen, Yuanyuan Chen (), Xu Chen () and Bokai Zhu ()
Additional contact information
William Dion: University of Pittsburgh School of Medicine
Yuren Tao: University of California
Maci Chambers: University of Pittsburgh School of Medicine
Shanshan Zhao: University of California
Riley K. Arbuckle: University of Pittsburgh School of Medicine
Michelle Sun: University of Pittsburgh School of Medicine
Syeda Kubra: University of Pittsburgh School of Medicine
Matthew A. Schaich: University of Pittsburgh
Yuhang Nie: University of California
Megan Ye: University of Pittsburgh School of Medicine
Imran Jamal: University of Pittsburgh School of Medicine
Mads B. Larsen: University of Pittsburgh School of Medicine
Daniel Camarco: University of Pittsburgh School of Medicine
Eleanor Ickes: University of Pittsburgh School of Medicine
Haokun H. Wang: University of Pittsburgh School of Medicine
C. DuPont: University of Pittsburgh School of Medicine
Bingjie Wang: University of Pittsburgh School of Medicine
Silvia Liu: University of Pittsburgh School of Medicine
Shaohua Pi: University of Pittsburgh School of Medicine
Bennett Houten: University of Pittsburgh
Bill B. Chen: University of Pittsburgh School of Medicine
Yuanyuan Chen: University of Pittsburgh School of Medicine
Xu Chen: University of California
Bokai Zhu: University of Pittsburgh School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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 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.

Date: 2025
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DOI: 10.1038/s41467-025-62242-7

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